The Diagnosis: Metastatic Renal Cell Carcinoma

Histopathologic examination of the punch biopsy demonstrated epithelioid cells with abundant clear cytoplasm and numerous chicken wire-like vascular channels consistent with a diagnosis of cutaneous metastasis of renal cell carcinoma (RCC)(Figure). Collateral history revealed that 8 years prior, the patient had been diagnosed with clear cell RCC, stage III (T3aN0M0). At that time, he was treated with radical nephrectomy, which was considered curative. He remained disease free until several months prior to the development of the cutaneous lesion when he was found to have pulmonary and cerebral metastases with biopsies showing metastatic RCC. He was treated with lobectomy and Gamma Knife radiation for the lung and cerebral metastases, respectively. His oncologist planned to initiate therapy with the multikinase inhibitor sunitinib, which inhibits vascular endothelial growth factor (VEGF) signaling. Unfortunately, the patient died prior to treatment due to overwhelming tumor burden.

Clear cell RCC, the most common renal malignancy, presents with metastatic disease at the time of diagnosis in 21% of patients.¹ An additional 20% of patients with localized disease develop metastases within several years of receiving a nephrectomy without adjuvant therapy, which is standard treatment for stage I to stage III disease.^1,2 Metastatic RCC most frequently targets the lungs, bone, liver, and brain, though virtually any organ can be involved. Cutaneous involvement is estimated to occur in 3.3% of RCC cases,³ accounting for only 1.4% of cutaneous metastases overall.⁴ The risk for developing cutaneous metastases is greatest within 3 years following nephrectomy.³ However, our patient demonstrates that metastasis of RCC to skin can be long delayed (>5 years) despite an initial diagnosis of localized disease.

Cutaneous RCC classically presents as a painless firm papulonodule with a deep red or purple color due to its high vascularity.⁴ Several retrospective studies have identified the scalp as the most frequent site of cutaneous involvement, followed by the chest, abdomen, and nephrectomy scar.^3,4 The differential diagnosis includes other vascular lesions such as pyogenic granuloma, hemangioma, angiosarcoma, bacillary angiomatosis, and Kaposi sarcoma. Diagnosis usually is easily confirmed histologically. Proliferative nests of epithelioid cells with clear cell morphology are surrounded by delicately branching vessels referred to as chicken wire-like vasculature. Immunohistochemical studies demonstrate positivity for pan-cytokeratin, vimentin, and CD-10, and negativity for p63 and cytokeratins 5 and 6, helping to confirm the diagnosis in more challenging cases, especially when there is no known history of primary RCC.⁵

If cutaneous metastasis of RCC is diagnosed, a chest and abdominal computed tomography scan as well as serum alkaline phosphatase test are warranted, as up to 90% of patients with RCC in the skin have additional lesions in at least 1 other site such as the lungs, bones, or liver.³ Management of metastatic RCC includes surgical excision if a single metastasis is found and either immunotherapy with high-dose IL-2 or an anti-programmed cell death inhibitor. Patients with progressive disease also may receive targeted anti-VEGF inhibitors (eg, axitinib, pazopanib, sunitinib), which have been shown to increase progression-free survival in metastatic RCC.^6-8 Interestingly, some evidence suggests severely delayed recurrence of RCC (>5 years following nephrectomy) may predict better response to systemic therapy.⁹

This case of severely delayed metastasis of RCC 8 years after nephrectomy raises the question of whether routine surveillance for RCC recurrence should continue beyond 5 years. It also underscores the need for further studies to determine the utility of postsurgical adjuvant therapy for localized disease (stages I-III). A randomized clinical trial showed no significant difference in disease-free survival when the multikinase inhibitors sunitinib and sorafenib were used as adjuvant therapy.¹⁰ The randomized, placebo-controlled PROTECT trial showed no significant difference in disease-free survival between the VEGF inhibitor pazopanib and placebo when used as adjuvant therapy.¹¹ However, trials are ongoing to investigate a potential survival advantage of adjuvant therapy with the VEGF receptor inhibitor axitinib and the mammalian target of rapamycin inhibitor everolimus.

The Diagnosis: Metastatic Renal Cell Carcinoma

Histopathologic examination of the punch biopsy demonstrated epithelioid cells with abundant clear cytoplasm and numerous chicken wire-like vascular channels consistent with a diagnosis of cutaneous metastasis of renal cell carcinoma (RCC)(Figure). Collateral history revealed that 8 years prior, the patient had been diagnosed with clear cell RCC, stage III (T3aN0M0). At that time, he was treated with radical nephrectomy, which was considered curative. He remained disease free until several months prior to the development of the cutaneous lesion when he was found to have pulmonary and cerebral metastases with biopsies showing metastatic RCC. He was treated with lobectomy and Gamma Knife radiation for the lung and cerebral metastases, respectively. His oncologist planned to initiate therapy with the multikinase inhibitor sunitinib, which inhibits vascular endothelial growth factor (VEGF) signaling. Unfortunately, the patient died prior to treatment due to overwhelming tumor burden.

Clear cell RCC, the most common renal malignancy, presents with metastatic disease at the time of diagnosis in 21% of patients.¹ An additional 20% of patients with localized disease develop metastases within several years of receiving a nephrectomy without adjuvant therapy, which is standard treatment for stage I to stage III disease.^1,2 Metastatic RCC most frequently targets the lungs, bone, liver, and brain, though virtually any organ can be involved. Cutaneous involvement is estimated to occur in 3.3% of RCC cases,³ accounting for only 1.4% of cutaneous metastases overall.⁴ The risk for developing cutaneous metastases is greatest within 3 years following nephrectomy.³ However, our patient demonstrates that metastasis of RCC to skin can be long delayed (>5 years) despite an initial diagnosis of localized disease.

Cutaneous RCC classically presents as a painless firm papulonodule with a deep red or purple color due to its high vascularity.⁴ Several retrospective studies have identified the scalp as the most frequent site of cutaneous involvement, followed by the chest, abdomen, and nephrectomy scar.^3,4 The differential diagnosis includes other vascular lesions such as pyogenic granuloma, hemangioma, angiosarcoma, bacillary angiomatosis, and Kaposi sarcoma. Diagnosis usually is easily confirmed histologically. Proliferative nests of epithelioid cells with clear cell morphology are surrounded by delicately branching vessels referred to as chicken wire-like vasculature. Immunohistochemical studies demonstrate positivity for pan-cytokeratin, vimentin, and CD-10, and negativity for p63 and cytokeratins 5 and 6, helping to confirm the diagnosis in more challenging cases, especially when there is no known history of primary RCC.⁵

If cutaneous metastasis of RCC is diagnosed, a chest and abdominal computed tomography scan as well as serum alkaline phosphatase test are warranted, as up to 90% of patients with RCC in the skin have additional lesions in at least 1 other site such as the lungs, bones, or liver.³ Management of metastatic RCC includes surgical excision if a single metastasis is found and either immunotherapy with high-dose IL-2 or an anti-programmed cell death inhibitor. Patients with progressive disease also may receive targeted anti-VEGF inhibitors (eg, axitinib, pazopanib, sunitinib), which have been shown to increase progression-free survival in metastatic RCC.^6-8 Interestingly, some evidence suggests severely delayed recurrence of RCC (>5 years following nephrectomy) may predict better response to systemic therapy.⁹

This case of severely delayed metastasis of RCC 8 years after nephrectomy raises the question of whether routine surveillance for RCC recurrence should continue beyond 5 years. It also underscores the need for further studies to determine the utility of postsurgical adjuvant therapy for localized disease (stages I-III). A randomized clinical trial showed no significant difference in disease-free survival when the multikinase inhibitors sunitinib and sorafenib were used as adjuvant therapy.¹⁰ The randomized, placebo-controlled PROTECT trial showed no significant difference in disease-free survival between the VEGF inhibitor pazopanib and placebo when used as adjuvant therapy.¹¹ However, trials are ongoing to investigate a potential survival advantage of adjuvant therapy with the VEGF receptor inhibitor axitinib and the mammalian target of rapamycin inhibitor everolimus.

The Diagnosis: Metastatic Renal Cell Carcinoma

Histopathologic examination of the punch biopsy demonstrated epithelioid cells with abundant clear cytoplasm and numerous chicken wire-like vascular channels consistent with a diagnosis of cutaneous metastasis of renal cell carcinoma (RCC)(Figure). Collateral history revealed that 8 years prior, the patient had been diagnosed with clear cell RCC, stage III (T3aN0M0). At that time, he was treated with radical nephrectomy, which was considered curative. He remained disease free until several months prior to the development of the cutaneous lesion when he was found to have pulmonary and cerebral metastases with biopsies showing metastatic RCC. He was treated with lobectomy and Gamma Knife radiation for the lung and cerebral metastases, respectively. His oncologist planned to initiate therapy with the multikinase inhibitor sunitinib, which inhibits vascular endothelial growth factor (VEGF) signaling. Unfortunately, the patient died prior to treatment due to overwhelming tumor burden.

Clear cell RCC, the most common renal malignancy, presents with metastatic disease at the time of diagnosis in 21% of patients.¹ An additional 20% of patients with localized disease develop metastases within several years of receiving a nephrectomy without adjuvant therapy, which is standard treatment for stage I to stage III disease.^1,2 Metastatic RCC most frequently targets the lungs, bone, liver, and brain, though virtually any organ can be involved. Cutaneous involvement is estimated to occur in 3.3% of RCC cases,³ accounting for only 1.4% of cutaneous metastases overall.⁴ The risk for developing cutaneous metastases is greatest within 3 years following nephrectomy.³ However, our patient demonstrates that metastasis of RCC to skin can be long delayed (>5 years) despite an initial diagnosis of localized disease.

Cutaneous RCC classically presents as a painless firm papulonodule with a deep red or purple color due to its high vascularity.⁴ Several retrospective studies have identified the scalp as the most frequent site of cutaneous involvement, followed by the chest, abdomen, and nephrectomy scar.^3,4 The differential diagnosis includes other vascular lesions such as pyogenic granuloma, hemangioma, angiosarcoma, bacillary angiomatosis, and Kaposi sarcoma. Diagnosis usually is easily confirmed histologically. Proliferative nests of epithelioid cells with clear cell morphology are surrounded by delicately branching vessels referred to as chicken wire-like vasculature. Immunohistochemical studies demonstrate positivity for pan-cytokeratin, vimentin, and CD-10, and negativity for p63 and cytokeratins 5 and 6, helping to confirm the diagnosis in more challenging cases, especially when there is no known history of primary RCC.⁵

If cutaneous metastasis of RCC is diagnosed, a chest and abdominal computed tomography scan as well as serum alkaline phosphatase test are warranted, as up to 90% of patients with RCC in the skin have additional lesions in at least 1 other site such as the lungs, bones, or liver.³ Management of metastatic RCC includes surgical excision if a single metastasis is found and either immunotherapy with high-dose IL-2 or an anti-programmed cell death inhibitor. Patients with progressive disease also may receive targeted anti-VEGF inhibitors (eg, axitinib, pazopanib, sunitinib), which have been shown to increase progression-free survival in metastatic RCC.^6-8 Interestingly, some evidence suggests severely delayed recurrence of RCC (>5 years following nephrectomy) may predict better response to systemic therapy.⁹

This case of severely delayed metastasis of RCC 8 years after nephrectomy raises the question of whether routine surveillance for RCC recurrence should continue beyond 5 years. It also underscores the need for further studies to determine the utility of postsurgical adjuvant therapy for localized disease (stages I-III). A randomized clinical trial showed no significant difference in disease-free survival when the multikinase inhibitors sunitinib and sorafenib were used as adjuvant therapy.¹⁰ The randomized, placebo-controlled PROTECT trial showed no significant difference in disease-free survival between the VEGF inhibitor pazopanib and placebo when used as adjuvant therapy.¹¹ However, trials are ongoing to investigate a potential survival advantage of adjuvant therapy with the VEGF receptor inhibitor axitinib and the mammalian target of rapamycin inhibitor everolimus.

The eyes may be windows into a coming stroke, E&M visits may soon mean more money, many doctors still reach for the wrong atopic dermatitis tool, and misfolded proteins may plant the seed for multiple sclerosis.

Listen to the MDedge Daily News podcast for all the details on today’s top news.

The eyes may be windows into a coming stroke, E&M visits may soon mean more money, many doctors still reach for the wrong atopic dermatitis tool, and misfolded proteins may plant the seed for multiple sclerosis.

Listen to the MDedge Daily News podcast for all the details on today’s top news.

The eyes may be windows into a coming stroke, E&M visits may soon mean more money, many doctors still reach for the wrong atopic dermatitis tool, and misfolded proteins may plant the seed for multiple sclerosis.

Listen to the MDedge Daily News podcast for all the details on today’s top news.

The physician-patient relationship is an important component of patient care. In the last few years a new paradigm has emerged of instant communication. Because dermatologic diagnosis is visual, many patients feel that making a correct diagnosis is as easy as taking a quick look. The availability of smartphone photography and easy ways to get in touch with dermatologists have created a new reality in physician-patient communication, which sometimes may be abused. We conducted an email survey to assess the attitudes of Chilean dermatologists regarding new methods of communication with their patients.

A survey of 16 questions was distributed to all 343 members of the Chilean Society of Dermatology and Venerology from July 2016 to August 2016. A total of 147 (42.9%) dermatologists completed the survey. When asked if they use personal and direct communication with their patients outside of an office visit, 39% of respondents said always, 41% said sometimes, 17% said only in some circumstances, and 3% said never. Regarding the method of communication, 79% used personal email, 59% used mobile phones, 35% used corporate email, and 34% used text messages. Among respondents who gave their personal email address and phone number to patients, the primary reason stated was to be available for any kind of emergency (67%), for patient follow-up (57%), and for patients to feel close to their dermatologist (28%).

Sixty-nine percent of respondents said patients occasionally have requested to receive a diagnosis via a mobile messaging application, social networks, and email. Of them, 22% said they were very annoyed by these requests. When dermatologists were asked if these instant types of communication improved their relationship with patients, 30% said it does help and 36% said it does not; 30% said they do not know and 4% did not respond. If patients used personal methods of communication to contact their dermatologist that was considered outside of physician-patient boundaries, 63% of physician respondents said they kindly directed patients to formal ways of communication and 15% did not respond to such requests; 22% responded by informal methods of communication. Eighty-one percent of all respondents felt the limits of formal communication between physicians and patients have been surpassed.

To improve the quality of health care, many clinicians use modern methods of communication with their patients. Today, patients can turn to their physicians for medical advice by mobile phone or email. We attempted to characterize the attitudes of Chilean dermatologists regarding new ways of communicating with patients. Our results are similar to other studies. One analysis of primary care physicians in Geneva, Switzerland (N=372), showed that 72% gave their personal email address and 74% gave their mobile phone number to patients. The latter is higher than what was found in our study (59%), which may be explained by the fact that primary care physicians may need to maintain closer contact with their patients.¹

In another study performed in primary care physicians in Israel, physicians preferred to provide their mobile phone number rather than their personal email address because they felt that email communication was more likely to lead miscommunication than a phone call.² There are few reports on this subject in the international literature, and we believe cultural differences may be important when physicians confront these issues.

In general, patient satisfaction is high when patients can contact their physician by phone or email; however, new immediate forms of communication may lead to physician burnout, as patients expect immediate responses and solutions to their requests and healthy physician-patient boundaries may be surpassed. It is important to educate both patients and physicians on how these new tools may be properly used on both sides. New boundaries must be set.

The physician-patient relationship is an important component of patient care. In the last few years a new paradigm has emerged of instant communication. Because dermatologic diagnosis is visual, many patients feel that making a correct diagnosis is as easy as taking a quick look. The availability of smartphone photography and easy ways to get in touch with dermatologists have created a new reality in physician-patient communication, which sometimes may be abused. We conducted an email survey to assess the attitudes of Chilean dermatologists regarding new methods of communication with their patients.

A survey of 16 questions was distributed to all 343 members of the Chilean Society of Dermatology and Venerology from July 2016 to August 2016. A total of 147 (42.9%) dermatologists completed the survey. When asked if they use personal and direct communication with their patients outside of an office visit, 39% of respondents said always, 41% said sometimes, 17% said only in some circumstances, and 3% said never. Regarding the method of communication, 79% used personal email, 59% used mobile phones, 35% used corporate email, and 34% used text messages. Among respondents who gave their personal email address and phone number to patients, the primary reason stated was to be available for any kind of emergency (67%), for patient follow-up (57%), and for patients to feel close to their dermatologist (28%).

Sixty-nine percent of respondents said patients occasionally have requested to receive a diagnosis via a mobile messaging application, social networks, and email. Of them, 22% said they were very annoyed by these requests. When dermatologists were asked if these instant types of communication improved their relationship with patients, 30% said it does help and 36% said it does not; 30% said they do not know and 4% did not respond. If patients used personal methods of communication to contact their dermatologist that was considered outside of physician-patient boundaries, 63% of physician respondents said they kindly directed patients to formal ways of communication and 15% did not respond to such requests; 22% responded by informal methods of communication. Eighty-one percent of all respondents felt the limits of formal communication between physicians and patients have been surpassed.

To improve the quality of health care, many clinicians use modern methods of communication with their patients. Today, patients can turn to their physicians for medical advice by mobile phone or email. We attempted to characterize the attitudes of Chilean dermatologists regarding new ways of communicating with patients. Our results are similar to other studies. One analysis of primary care physicians in Geneva, Switzerland (N=372), showed that 72% gave their personal email address and 74% gave their mobile phone number to patients. The latter is higher than what was found in our study (59%), which may be explained by the fact that primary care physicians may need to maintain closer contact with their patients.¹

In another study performed in primary care physicians in Israel, physicians preferred to provide their mobile phone number rather than their personal email address because they felt that email communication was more likely to lead miscommunication than a phone call.² There are few reports on this subject in the international literature, and we believe cultural differences may be important when physicians confront these issues.

In general, patient satisfaction is high when patients can contact their physician by phone or email; however, new immediate forms of communication may lead to physician burnout, as patients expect immediate responses and solutions to their requests and healthy physician-patient boundaries may be surpassed. It is important to educate both patients and physicians on how these new tools may be properly used on both sides. New boundaries must be set.

The physician-patient relationship is an important component of patient care. In the last few years a new paradigm has emerged of instant communication. Because dermatologic diagnosis is visual, many patients feel that making a correct diagnosis is as easy as taking a quick look. The availability of smartphone photography and easy ways to get in touch with dermatologists have created a new reality in physician-patient communication, which sometimes may be abused. We conducted an email survey to assess the attitudes of Chilean dermatologists regarding new methods of communication with their patients.

A survey of 16 questions was distributed to all 343 members of the Chilean Society of Dermatology and Venerology from July 2016 to August 2016. A total of 147 (42.9%) dermatologists completed the survey. When asked if they use personal and direct communication with their patients outside of an office visit, 39% of respondents said always, 41% said sometimes, 17% said only in some circumstances, and 3% said never. Regarding the method of communication, 79% used personal email, 59% used mobile phones, 35% used corporate email, and 34% used text messages. Among respondents who gave their personal email address and phone number to patients, the primary reason stated was to be available for any kind of emergency (67%), for patient follow-up (57%), and for patients to feel close to their dermatologist (28%).

Sixty-nine percent of respondents said patients occasionally have requested to receive a diagnosis via a mobile messaging application, social networks, and email. Of them, 22% said they were very annoyed by these requests. When dermatologists were asked if these instant types of communication improved their relationship with patients, 30% said it does help and 36% said it does not; 30% said they do not know and 4% did not respond. If patients used personal methods of communication to contact their dermatologist that was considered outside of physician-patient boundaries, 63% of physician respondents said they kindly directed patients to formal ways of communication and 15% did not respond to such requests; 22% responded by informal methods of communication. Eighty-one percent of all respondents felt the limits of formal communication between physicians and patients have been surpassed.

To improve the quality of health care, many clinicians use modern methods of communication with their patients. Today, patients can turn to their physicians for medical advice by mobile phone or email. We attempted to characterize the attitudes of Chilean dermatologists regarding new ways of communicating with patients. Our results are similar to other studies. One analysis of primary care physicians in Geneva, Switzerland (N=372), showed that 72% gave their personal email address and 74% gave their mobile phone number to patients. The latter is higher than what was found in our study (59%), which may be explained by the fact that primary care physicians may need to maintain closer contact with their patients.¹

In another study performed in primary care physicians in Israel, physicians preferred to provide their mobile phone number rather than their personal email address because they felt that email communication was more likely to lead miscommunication than a phone call.² There are few reports on this subject in the international literature, and we believe cultural differences may be important when physicians confront these issues.

In general, patient satisfaction is high when patients can contact their physician by phone or email; however, new immediate forms of communication may lead to physician burnout, as patients expect immediate responses and solutions to their requests and healthy physician-patient boundaries may be surpassed. It is important to educate both patients and physicians on how these new tools may be properly used on both sides. New boundaries must be set.

Introduction

Polycythemia vera (PV) and essential thrombocythemia (ET), along with primary myelofibrosis (PMF), belong to the group of Philadelphia-negative myeloproliferative neoplasms (MPN). All these malignancies arise from the clonal proliferation of an aberrant hematopoietic stem cell, but are characterized by distinct clinical phenotypes.^1,2 Although the clinical course of PV and ET is indolent, it can be complicated by thrombohemorrhagic episodes and/or evolution into myelofibrosis and/or acute myeloid leukemia (AML).³ Since vascular events are the most frequent life-threatening complications of PV and ET, therapeutic strategies are aimed at reducing this risk. Treatment may also help control other disease-associated symptoms.⁴ No therapy has been shown to prevent evolution of PV or ET into myelofibrosis or AML. The discovery of the Janus kinase 2 (JAK2)/V617F mutation in most patients with PV and over half of those with ET (and PMF)^5,6 has opened new avenues of research and led to the development of targeted therapies, such as the JAK1/2 inhibitor ruxolitinib, for patients with MPN.^7,8

Epidemiology

PV and ET are typically diagnosed in the fifth to seventh decade of life.⁹ Although these disorders are generally associated with a long clinical course, survival of patients with PV or ET may be shorter than that of the general population.^10–13 Estimating the incidence and prevalence of MPN is a challenge because most patients remain asymptomatic for long periods of time and do not seek medical attention.¹³ The annual incidence rates of PV and ET are estimated at 0.01 to 2.61 and 0.21 to 2.53 per 100,000, respectively. PV occurs slightly more frequently in males, whereas ET has a predilection for females.¹⁴ Given the long course and low mortality associated with these disorders, the prevalence of PV and ET are significantly higher than the respective incidence: up to 47 and 57 per 100,000, respectively.^15–17

Molecular Pathogenesis

In 2005 researchers discovered a gain-of-function mutation of the JAK2 gene in nearly all patients with PV and more than half of those with ET and PMF.^5,6,18,19 JAK2 is a non-receptor tyrosine kinase that plays a central role in normal hematopoiesis. Substitution of a valine for a phenylalanine at codon 617 (ie, V617F) leads to its constitutive activation and signaling through the JAK-STAT pathway.^5,6,18,19 More rarely (and exclusively in patients with PV), JAK2 mutations involve exon 12.^20–22 The vast majority of JAK2-negative ET patients harbor mutations in either the myeloproliferative leukemia (MPL) gene, which encodes the thrombopoietin receptor,^23–25 or the calreticulin (CALR) gene,^26,27 which encodes for a chaperone protein that plays a role in cellular proliferation, differentiation, and apoptosis.²⁸ Both the MPL and CALR mutations ultimately result in the constitutive activation of the JAK-STAT pathway. Thus, JAK2, MPL, and CALR alterations are collectively referred to as driver mutations. Moreover, because these mutations affect the same oncogenic pathway (ie, JAK-STAT), they are almost always mutually exclusive in a given patient. Patients with ET (or myelofibrosis) who are wild-type for JAK2, MPL, and CALR are referred to as having “triple-negative” disease. Many recurrent non-driver mutations are also found in patients with MPN that are not exclusive of each other (ie, patients may have many at the same time), and involve for example ten-eleven translocation-2 (TET2), additional sex combs like 1 (ASXL1), enhancer of zeste homolog 2 (EZH2), isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (IDH1/2), and DNA methyltransferase 3A (DNMT3A) genes, among others.²⁹ The biologic and prognostic significance of these non-driver alterations remain to be fully defined in ET and PV.

Diagnosis and Risk Assessment

Case Presentations

Patient A is a 68-year-old man with a history of gouty arthritis who presents with a 6-month history of recurrent headaches and itching that increases after a hot shower. Over the past 2 months, he has also noticed worsening fatigue and redness of his face. He is a nonsmoker. Physical exam reveals erythromelalgia (ie, erythema, edema, and warmth) of the upper and lower extremities, scattered scratch marks, and splenomegaly 4 cm below the costal margin. Complete blood count (CBC) shows a white blood cell (WBC) count of 8100/µL, hemoglobin 194 g/L, and platelets 582 × 10³/µL. Serum erythropoietin level is decreased at 2 mU/mL. Peripheral blood testing reveals a JAK2V617F mutation.

Patient B is a 51-year-old woman with a history of severe depression treated with sertraline and hypertension controlled with lisinopril and amlodipine who presents to her primary care physician for her “50-year-old physical.” She denies symptoms and is a nonsmoker. Physical exam is unrevealing. CBC shows a WBC count of 7400/µL (normal differential), hemoglobin 135 g/L, and platelets 1282 × 10³/µL. A bone marrow biopsy shows normal cellularity with clusters of large, hyperlobulated megakaryocytes. Reverse transcriptase-polymerase chain reaction fails to reveal a BCR-ABL fusion product. The patient is diagnosed with ET.

Diagnostic Criteria

Diagnostic criteria for PV and ET according to the World Health Organization (WHO) classification³⁰ are summarized in Table 1. Criteria for the diagnosis of prefibrotic myelofibrosis are included as well since this entity was formally recognized as separate from ET and part of the PMF spectrum in the 2016 WHO classification of myeloid tumors.³⁰

Risk Stratification

Thrombohemorrhagic events, evolution into myelofibrosis, and leukemic transformation are the most serious complications in the course of PV or ET. Only thrombohemorrhagic events are, at least partially, preventable. Arterial or venous thrombotic complications are observed at rates of 1.8 to 10.9 per 100 patient-years in PV (arterial thrombosis being more common than venous) and 0.74 to 7.7 per 100 patient-years in ET, depending on the risk group³⁵ and the presence of other factors (see below).

Thrombosis Risk Stratification in PV

The risk stratification of patients with PV is based on 2 factors: age ≥ 60 years and prior history of thrombosis. If either is present the patient is assigned to the high-risk category, whereas if none is present the patient is considered at low risk.³⁶ In addition, high hematocrit³⁷ and high WBC,³⁸ but not thrombocytosis, have been associated with the development of vascular complications. In one study, the risk of new arterial thrombosis was increased by the presence of leukoerythroblastosis, hypertension, and prior arterial thrombosis, while karyotypic abnormalities and prior venous thrombosis were predictors of new venous thrombosis.³⁹ Another emerging risk factor for thrombosis in patients with PV is high JAK2 allele burden (ie, the normal-to-mutated gene product ratio), although the evidence supporting this conclusion is equivocal.⁴⁰

Thrombosis Risk Stratification in ET

Traditionally, in ET patients, thrombotic risk was assessed using the same 2 factors (age ≥ 60 years and prior history of thrombosis), separating patients into low- and high-risk groups. However, the prognostication of ET patients has been refined recently with the identification of new relevant factors. In particular, the impact of JAK2 mutations on thrombotic risk has been thoroughly studied. Clinically, the presence of JAK2V617F is associated with older age, higher hemoglobin and hematocrit, lower platelet counts, more frequent need for cytoreductive treatment, and greater tendency to evolve into PV (a rare event).^41,42 Many,^41,43–46 but not all,^47–51 studies suggested a correlation between JAK2 mutation and risk of both arterial and venous thrombosis. Although infrequent, a JAK2V617F homozygous state (ie, the mutation is present in both alleles) might confer an even higher thrombotic risk.⁵² Moreover, the impact of the JAK2 mutation on vascular events persists over time,⁵³ particularly in patients with high or unstable mutation burden.⁵⁴ Based on JAK2V617F’s influence on the thrombotic risk of ET patients, a new prognostic score was proposed, the International Prognostic Score for ET (IPSET)-thrombosis (Table 2). The revised version of this model is currently endorsed by the National Comprehensive Cancer Network and divides patients into 4 risk groups: high, intermediate, low, and very low. Treatment recommendations vary according to the risk group (as described below).⁵⁵

Other thrombotic risk factors have been identified, but deemed not significant enough to be included in the model. Cardiovascular risk factors (hypercholesterolemia, hypertension, smoking, diabetes mellitus) can increase the risk of vascular events,^56–59 as can splenomegaly⁶⁰ and baseline or persistent leukocytosis.^61–63 Thrombocytosis has been correlated with thrombotic risk in some studies,^64–68 whereas others did not support this conclusion and/or suggested a lower rate of thrombosis and, in some cases, increased risk of bleeding in ET patients with platelet counts greater than 1000 × 10³/µL (due to acquired von Willebrand syndrome).^{56,61,63,68,69}

CALR mutations tend to occur in younger males with lower hemoglobin and WBC count, higher platelet count, and greater marrow megakaryocytic predominance as compared to JAK2 mutations.^{26,27,70–72} The associated incidence of thrombosis was less than 10% at 15 years in patients with CALR mutations, lower than the incidence reported for ET patients with JAK2V617F mutations.⁷³ The presence of the mutation per se does not appear to affect the thrombotic risk.^74–76 Information on the thrombotic risk associated with MPL mutations or a triple-negative state is scarce. In both instances, however, the risk appears to be lower than with the JAK2 mutation.^73,77–79

Venous thromboembolism in patients with PV or ET may occur at unusual sites, such as the splanchnic or cerebral venous systems.⁸⁰ Risk factors for unusual venous thromboembolism include younger age,⁸¹ female gender (especially with concomitant use of oral contraceptive pills),⁸² and splenomegaly/splenectomy.⁸³JAK2 mutation has also been associated with thrombosis at unusual sites. However, the prevalence of MPN or JAK2V617F in patients presenting with splanchnic venous thromboembolism has varied.⁸⁰ In addition, MPN may be occult (ie, no clinical or laboratory abnormalities) in around 15% of patients.⁸⁴ Screening for JAK2V617F and underlying MPN is recommended in patients presenting with isolated unexplained splanchnic venous thromboembolism. Treatment entails long-term anticoagulation therapy. JAK2V617F screening in patients with nonsplanchnic venous thromboembolism is not recommended, as its prevalence in this group is low (< 3%).^85,86

Treatment

Cases Continued

Patient A is diagnosed with PV based on the presence of 2 major criteria (elevated hemoglobin and presence of the JAK2V617F mutation) and 1 minor criterion (low erythropoietin level). Given his age, he belongs to the high-risk disease category. He is now seeking advice regarding the management of his newly diagnosed PV.

Patient B presents to the emergency department with right lower extremity swelling and is found to have deep femoral thrombosis extending to the iliac vein. Five days after being discharged from the emergency department, she presents for follow-up. She is taking warfarin compliantly and her INR is within therapeutic range. The patient now has high-risk ET and would like to know more about thrombosis in her condition and how to best manage her risk.

Risk-Adapted Therapy

Low-Risk PV

All patients with PV should receive counseling to mitigate cardiovascular risk factors, including smoking cessation, lifestyle modifications, and lipid-lowering therapy, as indicated. Furthermore, all PV patients should receive acetylsalicylic acid (ASA) to decrease their risk for thrombosis and control vasomotor symptoms.^55,87 Aspirin 81 to 100 mg daily is the preferred regimen because it provides adequate antithrombotic effect without the associated bleeding risk of higher-dose aspirin.⁸⁸ Low-risk PV patients should also receive periodic phlebotomies to reduce and maintain their hematocrit below 45%. This recommendation is based on the results of the Cytoreductive Therapy in Polycythemia Vera (CYTO PV) randomized controlled trial. In the CYTO PV study, patients receiving more intense therapy to maintain the hematocrit below 45% had a lower incidence of cardiovascular-related deaths or major thrombotic events than those with hematocrit goals of 45% to 50% (2.7% versus 9.8%).⁸⁹ Cytoreduction is an option for low-risk patients who do not tolerate phlebotomy or require frequent phlebotomy, or who have disease-related bleeding, severe symptoms, symptomatic splenomegaly, or progressive leukocytosis.³⁸

High-Risk PV

Patients older than 60 years and/or with a history of thrombosis should be considered for cytoreductive therapy in addition to the above measures. Front-line cytoreductive therapies include hydroxyurea or interferon (IFN)- alfa.⁸⁷ Hydroxyurea is a potent ribonucleotide reductase inhibitor that interferes with DNA repair and is the treatment of choice for most high-risk patients with PV.⁹⁰ In a small trial hydroxyurea reduced the risk of thrombosis compared with historical controls treated with phlebotomy alone.⁹¹ Hydroxyurea is generally well tolerated; common side effects include cytopenias, nail changes, and mucosal and/or skin ulcers. Although never formally proven to be leukemogenic, this agent should be used with caution in younger patients.⁸⁷ Indeed, in the original study, the rates of transformation were 5.9% and 1.5% for patients receiving hydroxyurea and phlebotomy alone,⁹² respectively, although an independent role for hydroxyurea in leukemic transformation was not supported in the much larger European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) study.⁹³ About 70% of patients will have a sustained response to hydroxyurea,⁹⁴ while the remaining patients become resistant to or intolerant of the drug. Resistant individuals have a higher risk of progression to acute leukemia and death.⁹⁵

IFN alfa is a pleiotropic antitumor agent that has found application in many types of malignancies⁹⁶ and is sometimes employed as treatment for patients with newly diagnosed high-risk PV. Early studies showed responses in up to 100% of cases,^97,98 albeit at the expense of a high discontinuation rate due to adverse events, such as flu-like symptoms, fatigue, and neuropsychiatric manifestations.⁹⁹ A newer formulation of the drug obtained by adding a polyethylene glycol (PEG) moiety to the native IFN alfa molecule (PEG-IFN alfa) was shown to have a longer half-life, greater stability, less immunogenicity, and, potentially, better tolerability.¹⁰⁰ Pilot phase 2 trials of PEG-IFN alfa-2a demonstrated its remarkable activity, with symptomatic and hematologic responses seen in the majority of patients (which, in some cases, persisted beyond discontinuation), and reasonable tolerability, with long-term discontinuation rates of around 20% to 30%.^101–103 In some patients JAK2V617F became undetectable over time.¹⁰⁴ Results of 2 ongoing trials, MDP-RC111 (single-arm study, PEG-IFN alfa-2a in high-risk PV or ET [NCT01259817]) and MPD-RC112 (randomized controlled trial, PEG-IFN alfa-2a versus hydroxyurea in the same population [NCT01258856]), will shed light on the role of PEG-IFN alfa in the management of patients with high-risk PV or ET. In 2 phase 2 studies of PEG-IFN alfa-2b, complete responses were seen in 70% to 100% of patients and discontinuation occurred in around a third of cases.^105,106 A new, longer-acting formulation of PEG-IFN alfa-2a (peg-proline INF alfa-2b, AOP2014) is also undergoing clinical development.^107,108

The approach to treatment of PV based on thrombotic risk level is illustrated in Figure 1.

Very Low- and Low-Risk ET

Like patients with PV, individuals with ET should undergo rigorous cardiovascular risk management and generally receive ASA to decrease their thrombotic risk and improve symptom control. Antiplatelet therapy may not be warranted in patients with documented acquired von Willebrand syndrome, with or without extreme thrombocytosis, or in those in the very low-risk category according to the IPSET-thrombosis model.^55,87 The risk/benefit ratio of antiplatelet agents in patients with ET at different thrombotic risk levels was assessed in poor-quality studies and thus remains highly uncertain. Platelet-lowering agents are sometimes recommended in patients with low-risk disease who have platelet counts ≥ 1500 × 10³/µL, due to the potential risk of acquired von Willebrand syndrome and a risk of bleeding (this would require stopping ASA).¹⁰⁹ Cytoreduction may also be used in low-risk patients with progressive symptoms despite ASA, symptomatic or progressive splenomegaly, and progressive leukocytosis.

Intermediate-Risk ET

This category includes patients older than 60 years but without thrombosis or JAK2 mutations. These individuals would have been considered high risk (and thus candidates for cytoreductive therapy) according to the traditional risk stratification. Guidelines currently recommend ASA as the sole therapy for these patients, while reserving cytoreduction for those who experience thrombosis (ie, become high-risk) or have uncontrolled vasomotor or general symptoms, symptomatic splenomegaly, symptomatic thrombocytosis, or progressive leukocytosis.

High-Risk ET

For patients with ET in need of cytoreductive therapy (ie, those with prior thrombosis or older than 60 years with a JAK2V617F mutation), first-line options include hydroxyurea, IFN, and anagrelide. Hydroxyurea remains the treatment of choice in the majority of patients.¹¹⁰ In a seminal study, 114 patients with ET were randomly assigned to either observation or hydroxyurea treatment with the goal of maintaining the platelet count below 600 × 10³/µL. At a median follow-up of 27 months, patients in the hydroxyurea group had a lower thrombosis rate (3.6% versus 24%, P = 0.003) and longer thrombosis-free survival, regardless of the use of antiplatelet drugs.⁶⁴

Anagrelide, a selective inhibitor of megakaryocytic differentiation and proliferation, was compared with hydroxyurea in patients with ET in 2 randomized trials. In the first (N = 809), the group receiving anagrelide had a higher risk of arterial thrombosis, major bleeding, and fibrotic evolution, but lower incidence of venous thrombosis. Hydroxyurea was better tolerated, mainly due to anagrelide-related cardiovascular adverse events.¹¹¹ As a result of this study, hydroxyurea is often preferred to anagrelide as front-line therapy for patients with newly diagnosed high-risk ET. In the second, more recent study (N = 259), however, the 2 agents proved equivalent in terms of major or minor arterial or venous thrombosis, as well as discontinuation rate.¹¹² The discrepancy between the 2 trials may be partly explained by the different ET diagnostic criteria used, with the latter only enrolling patients with WHO-defined true ET, while the former utilized Polycythemia Vera Study Group-ET diagnostic criteria that included patients with increases in other blood counts or varying degrees of marrow fibrosis.

Interferons were studied in ET in parallel with PV. PEG-IFN alfa-2a proved effective in patients with ET, with responses observed in 80% of patients.¹⁰³ PEG-IFN alfa-2b produced similar results, with responses in 70% to 90% of patients in small studies and discontinuation observed in 20% to 38% of cases.^105,106,113 Because the very long-term leukemogenic potential of hydroxyurea has remained somewhat uncertain, anagrelide or IFN might be preferable choices in younger patients.

The approach to treatment of ET based on thrombotic risk level is illustrated in Figure 2.

Assessing Response to Therapy

For both patients with PV and ET the endpoint of treatment set forth for clinical trials has been the achievement of a clinicohematologic response. However, studies have failed to show a correlation between response and reduction of the thrombohemorrhagic risk.¹¹⁴ Therefore, proposed clinical trial response criteria were revised to include absence of hemorrhagic or thrombotic events as part of the definition of response (Table 3).⁹⁴

Cases Continued

Patient A was initially treated with phlebotomies and his blood counts were subsequently controlled with hydroxyurea, which he took uninterruptedly at an average dose of 2.5 g daily. He also took ASA daily throughout. Now, 18 months after the start of therapy, he presents with a complaint of fatigue for the past 3 months, which more recently has been associated with recurrent itching. A repeat CBC shows a WBC count of 17,200/µL, hemoglobin 181 g/L, and platelets 940 × 10³/µL.

Patient B presents for scheduled follow-up. She has had no further thrombotic episodes. However, she spontaneously discontinued hydroxyurea 1 month ago because of worsening mouth ulcers that impaired her ability to eat even small meals. She seeks recommendations for further treatment options.

Approach to Patients Refractory to or Intolerant of First-Line Therapy

According to the European LeukemiaNet recommendations, an inadequate response to hydroxyurea in patients with PV (or myelofibrosis) is defined as a need for phlebotomy to maintain hematocrit below < 45%, platelet count > 400 × 10³/µL, and a WBC count > 10,000/µL, or failure to reduce splenomegaly > 10 cm by > 50% at a dose of ≥ 2 g/day or maximum tolerated dose. Historically, treatment options for patients with PV or ET who failed first-line therapy (most commonly hydroxyurea) have included alkylating agents, such as busulfan, chlorambucil, or pipobroman, and phosphorus (P)-32. However, the use of these drugs is limited by the associated risk of leukemic transformation.^93,115,116 The use of IFN (or anagrelide for ET) is often considered in patients previously treated with hydroxyurea, and vice versa.

Ruxolitinib is a JAK1 and JAK2 inhibitor currently approved for the treatment of PV patients refractory to or intolerant of hydroxyurea.⁷ Following promising results of a phase 2 trial,¹¹⁷ ruxolitinib 10 mg twice daily was compared with best available therapy in the pivotal RESPONSE trial (N = 222). Ruxolitinib proved superior in achieving hematocrit control, reduction of spleen volume, and improvement of symptoms. Grade 3-4 hematologic toxicity was infrequent and similar in the 2 arms.¹¹⁸ In addition, longer follow-up of that study suggested a lower rate of thrombotic events in patients receiving ruxolitinib (1.8 versus 8.2 per 100 patient-years).¹¹⁹ In a similarly designed randomized phase 3 study in PV patients without splenomegaly (RESPONSE-2), more patients in the ruxolitinib arm had hematocrit reduction without an increase in toxicity. Based on the results of the above studies, ruxolitinib can be considered a standard of care for second-line therapy in this post-hydroxyurea patient population.¹²⁰

Ruxolitinib is also being tested in patients with high-risk ET who have become resistant to, or were intolerant of hydroxyurea, but currently has no approved indication in this setting.^121,122 Common side effects of ruxolitinib include cytopenias (especially anemia), increased risk of infections, hyperlipidemia, and increased risk of non-melanoma skin cancer.

Novel Agents

Novel agents that have been studied in patients with PV and ET are histone deacetylase inhibitors, murine double minute 2 (MDM2, or HDM2 for their human counterpart) inhibitors (which restore the function of p53), Bcl-2 homology domain 3 mimetics such as navitoclax and venetoclax, and, for patients with ET, the telomerase inhibitor imetelstat.¹²³

Disease Evolution

Cases Continued

Patient A’s PV has been well controlled with PEG-IFN alfa-2a 90 μg subcutaneously weekly. However, he now presents with a complaint of worsening fatigue and early satiety. On exam the patient appears ill and splenomegaly is appreciated 12 cm below the costal margin. CBC shows a WBC count of 2600/µL, hemoglobin 73 g/L, and platelets 122 × 10³/µL. Peripheral blood smear reveals leukoerythroblastosis and dacro­cytosis. CBC 6 months ago was normal. A bone marrow biopsy is consistent with myelofibrosis.

After discontinuing hydroxyurea, patient B’s ET has been well controlled with anagrelide. However, for the past 4 weeks she has complained of severe fatigue and easy bruising. Physical exam reveals a pale, ill-appearing woman with scattered bruises. CBC shows a WBC count of 14,600/µL with 44% myeloblasts, hemoglobin 73 g/L, and platelets 22 × 10³/µL. CBC 6 months ago was normal. A bone marrow biopsy is consistent with leukemic transformation of ET.

Post-PV/Post-ET Myelofibrosis

Diagnostic criteria for post-PV and post-ET myelofibrosis are outlined in Table 4.

Leukemic Transformation

The presence of more than 20% blasts in peripheral blood or bone marrow in a patient with MPN defines leukemic transformation. This occurs in up to 5% to 10% of patients and may or may not be preceded by a myelofibrosis phase.¹²⁶ In cases of extramedullary transformation, a lower percentage of blasts can be seen in the bone marrow compared to the peripheral blood. The pathogenesis of leukemic transformation has remained elusive, but it is believed to be associated with genetic instability, which facilitates the acquisition of additional mutations, including those of TET2, ASXL1, EZH2 and DNMT3, IDH1/2, and TP53.¹²⁷

Clinical risk factors for leukemic transformation include advanced age, karyotypic abnormalities, prior therapy with alkylating agents or P-32, splenectomy, increased peripheral blood or bone marrow blasts, leukocytosis, anemia, thrombocytopenia, and cytogenetic abnormalities. Hydroxyurea, interferon, and ruxolitinib have not been shown to have leukemogenic potential thus far. Prognosis of leukemic transformation is uniformly poor and patient survival rarely exceeds 6 months.

There is no standard of care for leukemic transformation of MPN (MPN-LT). Treatment options range from low-intensity regimens to more aggressive AML-type induction chemotherapy. No strategy appears clearly superior to others.¹²⁸ Hematopoietic stem cell transplantation is the only therapy that provides clinically meaningful benefit to patients,¹²⁹ but it is applicable only to a minority of patients with chemosensitive disease and good performance status.¹³⁰ Notable experimental approaches to MPN–LT include hypomethylating agents, such as decitabine¹³¹ or azacitidine,¹³² with or without ruxolitinib.^133-135

Conclusion

PV and ET are rare, chronic myeloid disorders. Patients typically experience a long clinical course and enjoy near-normal quality of life if properly managed. The 2 most important life-limiting complications of PV and ET are thrombohemorrhagic events and myelofibrosis/AML transformation. Vascular events are at least in part preventable with counseling on risk factors, phlebotomy (for patients with PV), antiplatelet therapy, and cytoreduction with hydroxyurea, IFNs, or anagrelide (for patients with ET). In addition, ruxolitinib was recently approved for PV patients after hydroxyurea failure. PV/ET transformation in myelofibrosis or AML is part of the natural history of the disease and no therapy has been shown to prevent it. Treatment follows recommendations set forth for PMF and AML, but results are generally poorer and novel strategies are needed to improve patients’ outcomes.

Introduction

Polycythemia vera (PV) and essential thrombocythemia (ET), along with primary myelofibrosis (PMF), belong to the group of Philadelphia-negative myeloproliferative neoplasms (MPN). All these malignancies arise from the clonal proliferation of an aberrant hematopoietic stem cell, but are characterized by distinct clinical phenotypes.^1,2 Although the clinical course of PV and ET is indolent, it can be complicated by thrombohemorrhagic episodes and/or evolution into myelofibrosis and/or acute myeloid leukemia (AML).³ Since vascular events are the most frequent life-threatening complications of PV and ET, therapeutic strategies are aimed at reducing this risk. Treatment may also help control other disease-associated symptoms.⁴ No therapy has been shown to prevent evolution of PV or ET into myelofibrosis or AML. The discovery of the Janus kinase 2 (JAK2)/V617F mutation in most patients with PV and over half of those with ET (and PMF)^5,6 has opened new avenues of research and led to the development of targeted therapies, such as the JAK1/2 inhibitor ruxolitinib, for patients with MPN.^7,8

Epidemiology

PV and ET are typically diagnosed in the fifth to seventh decade of life.⁹ Although these disorders are generally associated with a long clinical course, survival of patients with PV or ET may be shorter than that of the general population.^10–13 Estimating the incidence and prevalence of MPN is a challenge because most patients remain asymptomatic for long periods of time and do not seek medical attention.¹³ The annual incidence rates of PV and ET are estimated at 0.01 to 2.61 and 0.21 to 2.53 per 100,000, respectively. PV occurs slightly more frequently in males, whereas ET has a predilection for females.¹⁴ Given the long course and low mortality associated with these disorders, the prevalence of PV and ET are significantly higher than the respective incidence: up to 47 and 57 per 100,000, respectively.^15–17

Molecular Pathogenesis

In 2005 researchers discovered a gain-of-function mutation of the JAK2 gene in nearly all patients with PV and more than half of those with ET and PMF.^5,6,18,19 JAK2 is a non-receptor tyrosine kinase that plays a central role in normal hematopoiesis. Substitution of a valine for a phenylalanine at codon 617 (ie, V617F) leads to its constitutive activation and signaling through the JAK-STAT pathway.^5,6,18,19 More rarely (and exclusively in patients with PV), JAK2 mutations involve exon 12.^20–22 The vast majority of JAK2-negative ET patients harbor mutations in either the myeloproliferative leukemia (MPL) gene, which encodes the thrombopoietin receptor,^23–25 or the calreticulin (CALR) gene,^26,27 which encodes for a chaperone protein that plays a role in cellular proliferation, differentiation, and apoptosis.²⁸ Both the MPL and CALR mutations ultimately result in the constitutive activation of the JAK-STAT pathway. Thus, JAK2, MPL, and CALR alterations are collectively referred to as driver mutations. Moreover, because these mutations affect the same oncogenic pathway (ie, JAK-STAT), they are almost always mutually exclusive in a given patient. Patients with ET (or myelofibrosis) who are wild-type for JAK2, MPL, and CALR are referred to as having “triple-negative” disease. Many recurrent non-driver mutations are also found in patients with MPN that are not exclusive of each other (ie, patients may have many at the same time), and involve for example ten-eleven translocation-2 (TET2), additional sex combs like 1 (ASXL1), enhancer of zeste homolog 2 (EZH2), isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (IDH1/2), and DNA methyltransferase 3A (DNMT3A) genes, among others.²⁹ The biologic and prognostic significance of these non-driver alterations remain to be fully defined in ET and PV.

Diagnosis and Risk Assessment

Case Presentations

Patient A is a 68-year-old man with a history of gouty arthritis who presents with a 6-month history of recurrent headaches and itching that increases after a hot shower. Over the past 2 months, he has also noticed worsening fatigue and redness of his face. He is a nonsmoker. Physical exam reveals erythromelalgia (ie, erythema, edema, and warmth) of the upper and lower extremities, scattered scratch marks, and splenomegaly 4 cm below the costal margin. Complete blood count (CBC) shows a white blood cell (WBC) count of 8100/µL, hemoglobin 194 g/L, and platelets 582 × 10³/µL. Serum erythropoietin level is decreased at 2 mU/mL. Peripheral blood testing reveals a JAK2V617F mutation.

Patient B is a 51-year-old woman with a history of severe depression treated with sertraline and hypertension controlled with lisinopril and amlodipine who presents to her primary care physician for her “50-year-old physical.” She denies symptoms and is a nonsmoker. Physical exam is unrevealing. CBC shows a WBC count of 7400/µL (normal differential), hemoglobin 135 g/L, and platelets 1282 × 10³/µL. A bone marrow biopsy shows normal cellularity with clusters of large, hyperlobulated megakaryocytes. Reverse transcriptase-polymerase chain reaction fails to reveal a BCR-ABL fusion product. The patient is diagnosed with ET.

Diagnostic Criteria

Diagnostic criteria for PV and ET according to the World Health Organization (WHO) classification³⁰ are summarized in Table 1. Criteria for the diagnosis of prefibrotic myelofibrosis are included as well since this entity was formally recognized as separate from ET and part of the PMF spectrum in the 2016 WHO classification of myeloid tumors.³⁰

Risk Stratification

Thrombohemorrhagic events, evolution into myelofibrosis, and leukemic transformation are the most serious complications in the course of PV or ET. Only thrombohemorrhagic events are, at least partially, preventable. Arterial or venous thrombotic complications are observed at rates of 1.8 to 10.9 per 100 patient-years in PV (arterial thrombosis being more common than venous) and 0.74 to 7.7 per 100 patient-years in ET, depending on the risk group³⁵ and the presence of other factors (see below).

Thrombosis Risk Stratification in PV

The risk stratification of patients with PV is based on 2 factors: age ≥ 60 years and prior history of thrombosis. If either is present the patient is assigned to the high-risk category, whereas if none is present the patient is considered at low risk.³⁶ In addition, high hematocrit³⁷ and high WBC,³⁸ but not thrombocytosis, have been associated with the development of vascular complications. In one study, the risk of new arterial thrombosis was increased by the presence of leukoerythroblastosis, hypertension, and prior arterial thrombosis, while karyotypic abnormalities and prior venous thrombosis were predictors of new venous thrombosis.³⁹ Another emerging risk factor for thrombosis in patients with PV is high JAK2 allele burden (ie, the normal-to-mutated gene product ratio), although the evidence supporting this conclusion is equivocal.⁴⁰

Thrombosis Risk Stratification in ET

Traditionally, in ET patients, thrombotic risk was assessed using the same 2 factors (age ≥ 60 years and prior history of thrombosis), separating patients into low- and high-risk groups. However, the prognostication of ET patients has been refined recently with the identification of new relevant factors. In particular, the impact of JAK2 mutations on thrombotic risk has been thoroughly studied. Clinically, the presence of JAK2V617F is associated with older age, higher hemoglobin and hematocrit, lower platelet counts, more frequent need for cytoreductive treatment, and greater tendency to evolve into PV (a rare event).^41,42 Many,^41,43–46 but not all,^47–51 studies suggested a correlation between JAK2 mutation and risk of both arterial and venous thrombosis. Although infrequent, a JAK2V617F homozygous state (ie, the mutation is present in both alleles) might confer an even higher thrombotic risk.⁵² Moreover, the impact of the JAK2 mutation on vascular events persists over time,⁵³ particularly in patients with high or unstable mutation burden.⁵⁴ Based on JAK2V617F’s influence on the thrombotic risk of ET patients, a new prognostic score was proposed, the International Prognostic Score for ET (IPSET)-thrombosis (Table 2). The revised version of this model is currently endorsed by the National Comprehensive Cancer Network and divides patients into 4 risk groups: high, intermediate, low, and very low. Treatment recommendations vary according to the risk group (as described below).⁵⁵

Other thrombotic risk factors have been identified, but deemed not significant enough to be included in the model. Cardiovascular risk factors (hypercholesterolemia, hypertension, smoking, diabetes mellitus) can increase the risk of vascular events,^56–59 as can splenomegaly⁶⁰ and baseline or persistent leukocytosis.^61–63 Thrombocytosis has been correlated with thrombotic risk in some studies,^64–68 whereas others did not support this conclusion and/or suggested a lower rate of thrombosis and, in some cases, increased risk of bleeding in ET patients with platelet counts greater than 1000 × 10³/µL (due to acquired von Willebrand syndrome).^{56,61,63,68,69}

CALR mutations tend to occur in younger males with lower hemoglobin and WBC count, higher platelet count, and greater marrow megakaryocytic predominance as compared to JAK2 mutations.^{26,27,70–72} The associated incidence of thrombosis was less than 10% at 15 years in patients with CALR mutations, lower than the incidence reported for ET patients with JAK2V617F mutations.⁷³ The presence of the mutation per se does not appear to affect the thrombotic risk.^74–76 Information on the thrombotic risk associated with MPL mutations or a triple-negative state is scarce. In both instances, however, the risk appears to be lower than with the JAK2 mutation.^73,77–79

Venous thromboembolism in patients with PV or ET may occur at unusual sites, such as the splanchnic or cerebral venous systems.⁸⁰ Risk factors for unusual venous thromboembolism include younger age,⁸¹ female gender (especially with concomitant use of oral contraceptive pills),⁸² and splenomegaly/splenectomy.⁸³JAK2 mutation has also been associated with thrombosis at unusual sites. However, the prevalence of MPN or JAK2V617F in patients presenting with splanchnic venous thromboembolism has varied.⁸⁰ In addition, MPN may be occult (ie, no clinical or laboratory abnormalities) in around 15% of patients.⁸⁴ Screening for JAK2V617F and underlying MPN is recommended in patients presenting with isolated unexplained splanchnic venous thromboembolism. Treatment entails long-term anticoagulation therapy. JAK2V617F screening in patients with nonsplanchnic venous thromboembolism is not recommended, as its prevalence in this group is low (< 3%).^85,86

Treatment

Cases Continued

Patient A is diagnosed with PV based on the presence of 2 major criteria (elevated hemoglobin and presence of the JAK2V617F mutation) and 1 minor criterion (low erythropoietin level). Given his age, he belongs to the high-risk disease category. He is now seeking advice regarding the management of his newly diagnosed PV.

Patient B presents to the emergency department with right lower extremity swelling and is found to have deep femoral thrombosis extending to the iliac vein. Five days after being discharged from the emergency department, she presents for follow-up. She is taking warfarin compliantly and her INR is within therapeutic range. The patient now has high-risk ET and would like to know more about thrombosis in her condition and how to best manage her risk.

Risk-Adapted Therapy

Low-Risk PV

All patients with PV should receive counseling to mitigate cardiovascular risk factors, including smoking cessation, lifestyle modifications, and lipid-lowering therapy, as indicated. Furthermore, all PV patients should receive acetylsalicylic acid (ASA) to decrease their risk for thrombosis and control vasomotor symptoms.^55,87 Aspirin 81 to 100 mg daily is the preferred regimen because it provides adequate antithrombotic effect without the associated bleeding risk of higher-dose aspirin.⁸⁸ Low-risk PV patients should also receive periodic phlebotomies to reduce and maintain their hematocrit below 45%. This recommendation is based on the results of the Cytoreductive Therapy in Polycythemia Vera (CYTO PV) randomized controlled trial. In the CYTO PV study, patients receiving more intense therapy to maintain the hematocrit below 45% had a lower incidence of cardiovascular-related deaths or major thrombotic events than those with hematocrit goals of 45% to 50% (2.7% versus 9.8%).⁸⁹ Cytoreduction is an option for low-risk patients who do not tolerate phlebotomy or require frequent phlebotomy, or who have disease-related bleeding, severe symptoms, symptomatic splenomegaly, or progressive leukocytosis.³⁸

High-Risk PV

Patients older than 60 years and/or with a history of thrombosis should be considered for cytoreductive therapy in addition to the above measures. Front-line cytoreductive therapies include hydroxyurea or interferon (IFN)- alfa.⁸⁷ Hydroxyurea is a potent ribonucleotide reductase inhibitor that interferes with DNA repair and is the treatment of choice for most high-risk patients with PV.⁹⁰ In a small trial hydroxyurea reduced the risk of thrombosis compared with historical controls treated with phlebotomy alone.⁹¹ Hydroxyurea is generally well tolerated; common side effects include cytopenias, nail changes, and mucosal and/or skin ulcers. Although never formally proven to be leukemogenic, this agent should be used with caution in younger patients.⁸⁷ Indeed, in the original study, the rates of transformation were 5.9% and 1.5% for patients receiving hydroxyurea and phlebotomy alone,⁹² respectively, although an independent role for hydroxyurea in leukemic transformation was not supported in the much larger European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) study.⁹³ About 70% of patients will have a sustained response to hydroxyurea,⁹⁴ while the remaining patients become resistant to or intolerant of the drug. Resistant individuals have a higher risk of progression to acute leukemia and death.⁹⁵

IFN alfa is a pleiotropic antitumor agent that has found application in many types of malignancies⁹⁶ and is sometimes employed as treatment for patients with newly diagnosed high-risk PV. Early studies showed responses in up to 100% of cases,^97,98 albeit at the expense of a high discontinuation rate due to adverse events, such as flu-like symptoms, fatigue, and neuropsychiatric manifestations.⁹⁹ A newer formulation of the drug obtained by adding a polyethylene glycol (PEG) moiety to the native IFN alfa molecule (PEG-IFN alfa) was shown to have a longer half-life, greater stability, less immunogenicity, and, potentially, better tolerability.¹⁰⁰ Pilot phase 2 trials of PEG-IFN alfa-2a demonstrated its remarkable activity, with symptomatic and hematologic responses seen in the majority of patients (which, in some cases, persisted beyond discontinuation), and reasonable tolerability, with long-term discontinuation rates of around 20% to 30%.^101–103 In some patients JAK2V617F became undetectable over time.¹⁰⁴ Results of 2 ongoing trials, MDP-RC111 (single-arm study, PEG-IFN alfa-2a in high-risk PV or ET [NCT01259817]) and MPD-RC112 (randomized controlled trial, PEG-IFN alfa-2a versus hydroxyurea in the same population [NCT01258856]), will shed light on the role of PEG-IFN alfa in the management of patients with high-risk PV or ET. In 2 phase 2 studies of PEG-IFN alfa-2b, complete responses were seen in 70% to 100% of patients and discontinuation occurred in around a third of cases.^105,106 A new, longer-acting formulation of PEG-IFN alfa-2a (peg-proline INF alfa-2b, AOP2014) is also undergoing clinical development.^107,108

The approach to treatment of PV based on thrombotic risk level is illustrated in Figure 1.

Very Low- and Low-Risk ET

Like patients with PV, individuals with ET should undergo rigorous cardiovascular risk management and generally receive ASA to decrease their thrombotic risk and improve symptom control. Antiplatelet therapy may not be warranted in patients with documented acquired von Willebrand syndrome, with or without extreme thrombocytosis, or in those in the very low-risk category according to the IPSET-thrombosis model.^55,87 The risk/benefit ratio of antiplatelet agents in patients with ET at different thrombotic risk levels was assessed in poor-quality studies and thus remains highly uncertain. Platelet-lowering agents are sometimes recommended in patients with low-risk disease who have platelet counts ≥ 1500 × 10³/µL, due to the potential risk of acquired von Willebrand syndrome and a risk of bleeding (this would require stopping ASA).¹⁰⁹ Cytoreduction may also be used in low-risk patients with progressive symptoms despite ASA, symptomatic or progressive splenomegaly, and progressive leukocytosis.

Intermediate-Risk ET

This category includes patients older than 60 years but without thrombosis or JAK2 mutations. These individuals would have been considered high risk (and thus candidates for cytoreductive therapy) according to the traditional risk stratification. Guidelines currently recommend ASA as the sole therapy for these patients, while reserving cytoreduction for those who experience thrombosis (ie, become high-risk) or have uncontrolled vasomotor or general symptoms, symptomatic splenomegaly, symptomatic thrombocytosis, or progressive leukocytosis.

High-Risk ET

For patients with ET in need of cytoreductive therapy (ie, those with prior thrombosis or older than 60 years with a JAK2V617F mutation), first-line options include hydroxyurea, IFN, and anagrelide. Hydroxyurea remains the treatment of choice in the majority of patients.¹¹⁰ In a seminal study, 114 patients with ET were randomly assigned to either observation or hydroxyurea treatment with the goal of maintaining the platelet count below 600 × 10³/µL. At a median follow-up of 27 months, patients in the hydroxyurea group had a lower thrombosis rate (3.6% versus 24%, P = 0.003) and longer thrombosis-free survival, regardless of the use of antiplatelet drugs.⁶⁴

Anagrelide, a selective inhibitor of megakaryocytic differentiation and proliferation, was compared with hydroxyurea in patients with ET in 2 randomized trials. In the first (N = 809), the group receiving anagrelide had a higher risk of arterial thrombosis, major bleeding, and fibrotic evolution, but lower incidence of venous thrombosis. Hydroxyurea was better tolerated, mainly due to anagrelide-related cardiovascular adverse events.¹¹¹ As a result of this study, hydroxyurea is often preferred to anagrelide as front-line therapy for patients with newly diagnosed high-risk ET. In the second, more recent study (N = 259), however, the 2 agents proved equivalent in terms of major or minor arterial or venous thrombosis, as well as discontinuation rate.¹¹² The discrepancy between the 2 trials may be partly explained by the different ET diagnostic criteria used, with the latter only enrolling patients with WHO-defined true ET, while the former utilized Polycythemia Vera Study Group-ET diagnostic criteria that included patients with increases in other blood counts or varying degrees of marrow fibrosis.

Interferons were studied in ET in parallel with PV. PEG-IFN alfa-2a proved effective in patients with ET, with responses observed in 80% of patients.¹⁰³ PEG-IFN alfa-2b produced similar results, with responses in 70% to 90% of patients in small studies and discontinuation observed in 20% to 38% of cases.^105,106,113 Because the very long-term leukemogenic potential of hydroxyurea has remained somewhat uncertain, anagrelide or IFN might be preferable choices in younger patients.

The approach to treatment of ET based on thrombotic risk level is illustrated in Figure 2.

Assessing Response to Therapy

For both patients with PV and ET the endpoint of treatment set forth for clinical trials has been the achievement of a clinicohematologic response. However, studies have failed to show a correlation between response and reduction of the thrombohemorrhagic risk.¹¹⁴ Therefore, proposed clinical trial response criteria were revised to include absence of hemorrhagic or thrombotic events as part of the definition of response (Table 3).⁹⁴

Cases Continued

Patient A was initially treated with phlebotomies and his blood counts were subsequently controlled with hydroxyurea, which he took uninterruptedly at an average dose of 2.5 g daily. He also took ASA daily throughout. Now, 18 months after the start of therapy, he presents with a complaint of fatigue for the past 3 months, which more recently has been associated with recurrent itching. A repeat CBC shows a WBC count of 17,200/µL, hemoglobin 181 g/L, and platelets 940 × 10³/µL.

Patient B presents for scheduled follow-up. She has had no further thrombotic episodes. However, she spontaneously discontinued hydroxyurea 1 month ago because of worsening mouth ulcers that impaired her ability to eat even small meals. She seeks recommendations for further treatment options.

Approach to Patients Refractory to or Intolerant of First-Line Therapy

According to the European LeukemiaNet recommendations, an inadequate response to hydroxyurea in patients with PV (or myelofibrosis) is defined as a need for phlebotomy to maintain hematocrit below < 45%, platelet count > 400 × 10³/µL, and a WBC count > 10,000/µL, or failure to reduce splenomegaly > 10 cm by > 50% at a dose of ≥ 2 g/day or maximum tolerated dose. Historically, treatment options for patients with PV or ET who failed first-line therapy (most commonly hydroxyurea) have included alkylating agents, such as busulfan, chlorambucil, or pipobroman, and phosphorus (P)-32. However, the use of these drugs is limited by the associated risk of leukemic transformation.^93,115,116 The use of IFN (or anagrelide for ET) is often considered in patients previously treated with hydroxyurea, and vice versa.

Ruxolitinib is a JAK1 and JAK2 inhibitor currently approved for the treatment of PV patients refractory to or intolerant of hydroxyurea.⁷ Following promising results of a phase 2 trial,¹¹⁷ ruxolitinib 10 mg twice daily was compared with best available therapy in the pivotal RESPONSE trial (N = 222). Ruxolitinib proved superior in achieving hematocrit control, reduction of spleen volume, and improvement of symptoms. Grade 3-4 hematologic toxicity was infrequent and similar in the 2 arms.¹¹⁸ In addition, longer follow-up of that study suggested a lower rate of thrombotic events in patients receiving ruxolitinib (1.8 versus 8.2 per 100 patient-years).¹¹⁹ In a similarly designed randomized phase 3 study in PV patients without splenomegaly (RESPONSE-2), more patients in the ruxolitinib arm had hematocrit reduction without an increase in toxicity. Based on the results of the above studies, ruxolitinib can be considered a standard of care for second-line therapy in this post-hydroxyurea patient population.¹²⁰

Ruxolitinib is also being tested in patients with high-risk ET who have become resistant to, or were intolerant of hydroxyurea, but currently has no approved indication in this setting.^121,122 Common side effects of ruxolitinib include cytopenias (especially anemia), increased risk of infections, hyperlipidemia, and increased risk of non-melanoma skin cancer.

Novel Agents

Novel agents that have been studied in patients with PV and ET are histone deacetylase inhibitors, murine double minute 2 (MDM2, or HDM2 for their human counterpart) inhibitors (which restore the function of p53), Bcl-2 homology domain 3 mimetics such as navitoclax and venetoclax, and, for patients with ET, the telomerase inhibitor imetelstat.¹²³

Disease Evolution

Cases Continued

Patient A’s PV has been well controlled with PEG-IFN alfa-2a 90 μg subcutaneously weekly. However, he now presents with a complaint of worsening fatigue and early satiety. On exam the patient appears ill and splenomegaly is appreciated 12 cm below the costal margin. CBC shows a WBC count of 2600/µL, hemoglobin 73 g/L, and platelets 122 × 10³/µL. Peripheral blood smear reveals leukoerythroblastosis and dacro­cytosis. CBC 6 months ago was normal. A bone marrow biopsy is consistent with myelofibrosis.

After discontinuing hydroxyurea, patient B’s ET has been well controlled with anagrelide. However, for the past 4 weeks she has complained of severe fatigue and easy bruising. Physical exam reveals a pale, ill-appearing woman with scattered bruises. CBC shows a WBC count of 14,600/µL with 44% myeloblasts, hemoglobin 73 g/L, and platelets 22 × 10³/µL. CBC 6 months ago was normal. A bone marrow biopsy is consistent with leukemic transformation of ET.

Post-PV/Post-ET Myelofibrosis

Diagnostic criteria for post-PV and post-ET myelofibrosis are outlined in Table 4.

Leukemic Transformation

The presence of more than 20% blasts in peripheral blood or bone marrow in a patient with MPN defines leukemic transformation. This occurs in up to 5% to 10% of patients and may or may not be preceded by a myelofibrosis phase.¹²⁶ In cases of extramedullary transformation, a lower percentage of blasts can be seen in the bone marrow compared to the peripheral blood. The pathogenesis of leukemic transformation has remained elusive, but it is believed to be associated with genetic instability, which facilitates the acquisition of additional mutations, including those of TET2, ASXL1, EZH2 and DNMT3, IDH1/2, and TP53.¹²⁷

Clinical risk factors for leukemic transformation include advanced age, karyotypic abnormalities, prior therapy with alkylating agents or P-32, splenectomy, increased peripheral blood or bone marrow blasts, leukocytosis, anemia, thrombocytopenia, and cytogenetic abnormalities. Hydroxyurea, interferon, and ruxolitinib have not been shown to have leukemogenic potential thus far. Prognosis of leukemic transformation is uniformly poor and patient survival rarely exceeds 6 months.

There is no standard of care for leukemic transformation of MPN (MPN-LT). Treatment options range from low-intensity regimens to more aggressive AML-type induction chemotherapy. No strategy appears clearly superior to others.¹²⁸ Hematopoietic stem cell transplantation is the only therapy that provides clinically meaningful benefit to patients,¹²⁹ but it is applicable only to a minority of patients with chemosensitive disease and good performance status.¹³⁰ Notable experimental approaches to MPN–LT include hypomethylating agents, such as decitabine¹³¹ or azacitidine,¹³² with or without ruxolitinib.^133-135

Conclusion

PV and ET are rare, chronic myeloid disorders. Patients typically experience a long clinical course and enjoy near-normal quality of life if properly managed. The 2 most important life-limiting complications of PV and ET are thrombohemorrhagic events and myelofibrosis/AML transformation. Vascular events are at least in part preventable with counseling on risk factors, phlebotomy (for patients with PV), antiplatelet therapy, and cytoreduction with hydroxyurea, IFNs, or anagrelide (for patients with ET). In addition, ruxolitinib was recently approved for PV patients after hydroxyurea failure. PV/ET transformation in myelofibrosis or AML is part of the natural history of the disease and no therapy has been shown to prevent it. Treatment follows recommendations set forth for PMF and AML, but results are generally poorer and novel strategies are needed to improve patients’ outcomes.

Introduction

Polycythemia vera (PV) and essential thrombocythemia (ET), along with primary myelofibrosis (PMF), belong to the group of Philadelphia-negative myeloproliferative neoplasms (MPN). All these malignancies arise from the clonal proliferation of an aberrant hematopoietic stem cell, but are characterized by distinct clinical phenotypes.^1,2 Although the clinical course of PV and ET is indolent, it can be complicated by thrombohemorrhagic episodes and/or evolution into myelofibrosis and/or acute myeloid leukemia (AML).³ Since vascular events are the most frequent life-threatening complications of PV and ET, therapeutic strategies are aimed at reducing this risk. Treatment may also help control other disease-associated symptoms.⁴ No therapy has been shown to prevent evolution of PV or ET into myelofibrosis or AML. The discovery of the Janus kinase 2 (JAK2)/V617F mutation in most patients with PV and over half of those with ET (and PMF)^5,6 has opened new avenues of research and led to the development of targeted therapies, such as the JAK1/2 inhibitor ruxolitinib, for patients with MPN.^7,8

Epidemiology

PV and ET are typically diagnosed in the fifth to seventh decade of life.⁹ Although these disorders are generally associated with a long clinical course, survival of patients with PV or ET may be shorter than that of the general population.^10–13 Estimating the incidence and prevalence of MPN is a challenge because most patients remain asymptomatic for long periods of time and do not seek medical attention.¹³ The annual incidence rates of PV and ET are estimated at 0.01 to 2.61 and 0.21 to 2.53 per 100,000, respectively. PV occurs slightly more frequently in males, whereas ET has a predilection for females.¹⁴ Given the long course and low mortality associated with these disorders, the prevalence of PV and ET are significantly higher than the respective incidence: up to 47 and 57 per 100,000, respectively.^15–17

Molecular Pathogenesis

In 2005 researchers discovered a gain-of-function mutation of the JAK2 gene in nearly all patients with PV and more than half of those with ET and PMF.^5,6,18,19 JAK2 is a non-receptor tyrosine kinase that plays a central role in normal hematopoiesis. Substitution of a valine for a phenylalanine at codon 617 (ie, V617F) leads to its constitutive activation and signaling through the JAK-STAT pathway.^5,6,18,19 More rarely (and exclusively in patients with PV), JAK2 mutations involve exon 12.^20–22 The vast majority of JAK2-negative ET patients harbor mutations in either the myeloproliferative leukemia (MPL) gene, which encodes the thrombopoietin receptor,^23–25 or the calreticulin (CALR) gene,^26,27 which encodes for a chaperone protein that plays a role in cellular proliferation, differentiation, and apoptosis.²⁸ Both the MPL and CALR mutations ultimately result in the constitutive activation of the JAK-STAT pathway. Thus, JAK2, MPL, and CALR alterations are collectively referred to as driver mutations. Moreover, because these mutations affect the same oncogenic pathway (ie, JAK-STAT), they are almost always mutually exclusive in a given patient. Patients with ET (or myelofibrosis) who are wild-type for JAK2, MPL, and CALR are referred to as having “triple-negative” disease. Many recurrent non-driver mutations are also found in patients with MPN that are not exclusive of each other (ie, patients may have many at the same time), and involve for example ten-eleven translocation-2 (TET2), additional sex combs like 1 (ASXL1), enhancer of zeste homolog 2 (EZH2), isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (IDH1/2), and DNA methyltransferase 3A (DNMT3A) genes, among others.²⁹ The biologic and prognostic significance of these non-driver alterations remain to be fully defined in ET and PV.

Diagnosis and Risk Assessment

Case Presentations

Patient A is a 68-year-old man with a history of gouty arthritis who presents with a 6-month history of recurrent headaches and itching that increases after a hot shower. Over the past 2 months, he has also noticed worsening fatigue and redness of his face. He is a nonsmoker. Physical exam reveals erythromelalgia (ie, erythema, edema, and warmth) of the upper and lower extremities, scattered scratch marks, and splenomegaly 4 cm below the costal margin. Complete blood count (CBC) shows a white blood cell (WBC) count of 8100/µL, hemoglobin 194 g/L, and platelets 582 × 10³/µL. Serum erythropoietin level is decreased at 2 mU/mL. Peripheral blood testing reveals a JAK2V617F mutation.

Patient B is a 51-year-old woman with a history of severe depression treated with sertraline and hypertension controlled with lisinopril and amlodipine who presents to her primary care physician for her “50-year-old physical.” She denies symptoms and is a nonsmoker. Physical exam is unrevealing. CBC shows a WBC count of 7400/µL (normal differential), hemoglobin 135 g/L, and platelets 1282 × 10³/µL. A bone marrow biopsy shows normal cellularity with clusters of large, hyperlobulated megakaryocytes. Reverse transcriptase-polymerase chain reaction fails to reveal a BCR-ABL fusion product. The patient is diagnosed with ET.

Diagnostic Criteria

Diagnostic criteria for PV and ET according to the World Health Organization (WHO) classification³⁰ are summarized in Table 1. Criteria for the diagnosis of prefibrotic myelofibrosis are included as well since this entity was formally recognized as separate from ET and part of the PMF spectrum in the 2016 WHO classification of myeloid tumors.³⁰

Risk Stratification

Thrombohemorrhagic events, evolution into myelofibrosis, and leukemic transformation are the most serious complications in the course of PV or ET. Only thrombohemorrhagic events are, at least partially, preventable. Arterial or venous thrombotic complications are observed at rates of 1.8 to 10.9 per 100 patient-years in PV (arterial thrombosis being more common than venous) and 0.74 to 7.7 per 100 patient-years in ET, depending on the risk group³⁵ and the presence of other factors (see below).

Thrombosis Risk Stratification in PV

The risk stratification of patients with PV is based on 2 factors: age ≥ 60 years and prior history of thrombosis. If either is present the patient is assigned to the high-risk category, whereas if none is present the patient is considered at low risk.³⁶ In addition, high hematocrit³⁷ and high WBC,³⁸ but not thrombocytosis, have been associated with the development of vascular complications. In one study, the risk of new arterial thrombosis was increased by the presence of leukoerythroblastosis, hypertension, and prior arterial thrombosis, while karyotypic abnormalities and prior venous thrombosis were predictors of new venous thrombosis.³⁹ Another emerging risk factor for thrombosis in patients with PV is high JAK2 allele burden (ie, the normal-to-mutated gene product ratio), although the evidence supporting this conclusion is equivocal.⁴⁰

Thrombosis Risk Stratification in ET

Traditionally, in ET patients, thrombotic risk was assessed using the same 2 factors (age ≥ 60 years and prior history of thrombosis), separating patients into low- and high-risk groups. However, the prognostication of ET patients has been refined recently with the identification of new relevant factors. In particular, the impact of JAK2 mutations on thrombotic risk has been thoroughly studied. Clinically, the presence of JAK2V617F is associated with older age, higher hemoglobin and hematocrit, lower platelet counts, more frequent need for cytoreductive treatment, and greater tendency to evolve into PV (a rare event).^41,42 Many,^41,43–46 but not all,^47–51 studies suggested a correlation between JAK2 mutation and risk of both arterial and venous thrombosis. Although infrequent, a JAK2V617F homozygous state (ie, the mutation is present in both alleles) might confer an even higher thrombotic risk.⁵² Moreover, the impact of the JAK2 mutation on vascular events persists over time,⁵³ particularly in patients with high or unstable mutation burden.⁵⁴ Based on JAK2V617F’s influence on the thrombotic risk of ET patients, a new prognostic score was proposed, the International Prognostic Score for ET (IPSET)-thrombosis (Table 2). The revised version of this model is currently endorsed by the National Comprehensive Cancer Network and divides patients into 4 risk groups: high, intermediate, low, and very low. Treatment recommendations vary according to the risk group (as described below).⁵⁵

Other thrombotic risk factors have been identified, but deemed not significant enough to be included in the model. Cardiovascular risk factors (hypercholesterolemia, hypertension, smoking, diabetes mellitus) can increase the risk of vascular events,^56–59 as can splenomegaly⁶⁰ and baseline or persistent leukocytosis.^61–63 Thrombocytosis has been correlated with thrombotic risk in some studies,^64–68 whereas others did not support this conclusion and/or suggested a lower rate of thrombosis and, in some cases, increased risk of bleeding in ET patients with platelet counts greater than 1000 × 10³/µL (due to acquired von Willebrand syndrome).^{56,61,63,68,69}

CALR mutations tend to occur in younger males with lower hemoglobin and WBC count, higher platelet count, and greater marrow megakaryocytic predominance as compared to JAK2 mutations.^{26,27,70–72} The associated incidence of thrombosis was less than 10% at 15 years in patients with CALR mutations, lower than the incidence reported for ET patients with JAK2V617F mutations.⁷³ The presence of the mutation per se does not appear to affect the thrombotic risk.^74–76 Information on the thrombotic risk associated with MPL mutations or a triple-negative state is scarce. In both instances, however, the risk appears to be lower than with the JAK2 mutation.^73,77–79

Venous thromboembolism in patients with PV or ET may occur at unusual sites, such as the splanchnic or cerebral venous systems.⁸⁰ Risk factors for unusual venous thromboembolism include younger age,⁸¹ female gender (especially with concomitant use of oral contraceptive pills),⁸² and splenomegaly/splenectomy.⁸³JAK2 mutation has also been associated with thrombosis at unusual sites. However, the prevalence of MPN or JAK2V617F in patients presenting with splanchnic venous thromboembolism has varied.⁸⁰ In addition, MPN may be occult (ie, no clinical or laboratory abnormalities) in around 15% of patients.⁸⁴ Screening for JAK2V617F and underlying MPN is recommended in patients presenting with isolated unexplained splanchnic venous thromboembolism. Treatment entails long-term anticoagulation therapy. JAK2V617F screening in patients with nonsplanchnic venous thromboembolism is not recommended, as its prevalence in this group is low (< 3%).^85,86

Treatment

Cases Continued

Patient A is diagnosed with PV based on the presence of 2 major criteria (elevated hemoglobin and presence of the JAK2V617F mutation) and 1 minor criterion (low erythropoietin level). Given his age, he belongs to the high-risk disease category. He is now seeking advice regarding the management of his newly diagnosed PV.

Patient B presents to the emergency department with right lower extremity swelling and is found to have deep femoral thrombosis extending to the iliac vein. Five days after being discharged from the emergency department, she presents for follow-up. She is taking warfarin compliantly and her INR is within therapeutic range. The patient now has high-risk ET and would like to know more about thrombosis in her condition and how to best manage her risk.

Risk-Adapted Therapy

Low-Risk PV

All patients with PV should receive counseling to mitigate cardiovascular risk factors, including smoking cessation, lifestyle modifications, and lipid-lowering therapy, as indicated. Furthermore, all PV patients should receive acetylsalicylic acid (ASA) to decrease their risk for thrombosis and control vasomotor symptoms.^55,87 Aspirin 81 to 100 mg daily is the preferred regimen because it provides adequate antithrombotic effect without the associated bleeding risk of higher-dose aspirin.⁸⁸ Low-risk PV patients should also receive periodic phlebotomies to reduce and maintain their hematocrit below 45%. This recommendation is based on the results of the Cytoreductive Therapy in Polycythemia Vera (CYTO PV) randomized controlled trial. In the CYTO PV study, patients receiving more intense therapy to maintain the hematocrit below 45% had a lower incidence of cardiovascular-related deaths or major thrombotic events than those with hematocrit goals of 45% to 50% (2.7% versus 9.8%).⁸⁹ Cytoreduction is an option for low-risk patients who do not tolerate phlebotomy or require frequent phlebotomy, or who have disease-related bleeding, severe symptoms, symptomatic splenomegaly, or progressive leukocytosis.³⁸

High-Risk PV

Patients older than 60 years and/or with a history of thrombosis should be considered for cytoreductive therapy in addition to the above measures. Front-line cytoreductive therapies include hydroxyurea or interferon (IFN)- alfa.⁸⁷ Hydroxyurea is a potent ribonucleotide reductase inhibitor that interferes with DNA repair and is the treatment of choice for most high-risk patients with PV.⁹⁰ In a small trial hydroxyurea reduced the risk of thrombosis compared with historical controls treated with phlebotomy alone.⁹¹ Hydroxyurea is generally well tolerated; common side effects include cytopenias, nail changes, and mucosal and/or skin ulcers. Although never formally proven to be leukemogenic, this agent should be used with caution in younger patients.⁸⁷ Indeed, in the original study, the rates of transformation were 5.9% and 1.5% for patients receiving hydroxyurea and phlebotomy alone,⁹² respectively, although an independent role for hydroxyurea in leukemic transformation was not supported in the much larger European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) study.⁹³ About 70% of patients will have a sustained response to hydroxyurea,⁹⁴ while the remaining patients become resistant to or intolerant of the drug. Resistant individuals have a higher risk of progression to acute leukemia and death.⁹⁵

IFN alfa is a pleiotropic antitumor agent that has found application in many types of malignancies⁹⁶ and is sometimes employed as treatment for patients with newly diagnosed high-risk PV. Early studies showed responses in up to 100% of cases,^97,98 albeit at the expense of a high discontinuation rate due to adverse events, such as flu-like symptoms, fatigue, and neuropsychiatric manifestations.⁹⁹ A newer formulation of the drug obtained by adding a polyethylene glycol (PEG) moiety to the native IFN alfa molecule (PEG-IFN alfa) was shown to have a longer half-life, greater stability, less immunogenicity, and, potentially, better tolerability.¹⁰⁰ Pilot phase 2 trials of PEG-IFN alfa-2a demonstrated its remarkable activity, with symptomatic and hematologic responses seen in the majority of patients (which, in some cases, persisted beyond discontinuation), and reasonable tolerability, with long-term discontinuation rates of around 20% to 30%.^101–103 In some patients JAK2V617F became undetectable over time.¹⁰⁴ Results of 2 ongoing trials, MDP-RC111 (single-arm study, PEG-IFN alfa-2a in high-risk PV or ET [NCT01259817]) and MPD-RC112 (randomized controlled trial, PEG-IFN alfa-2a versus hydroxyurea in the same population [NCT01258856]), will shed light on the role of PEG-IFN alfa in the management of patients with high-risk PV or ET. In 2 phase 2 studies of PEG-IFN alfa-2b, complete responses were seen in 70% to 100% of patients and discontinuation occurred in around a third of cases.^105,106 A new, longer-acting formulation of PEG-IFN alfa-2a (peg-proline INF alfa-2b, AOP2014) is also undergoing clinical development.^107,108

The approach to treatment of PV based on thrombotic risk level is illustrated in Figure 1.

Very Low- and Low-Risk ET

Like patients with PV, individuals with ET should undergo rigorous cardiovascular risk management and generally receive ASA to decrease their thrombotic risk and improve symptom control. Antiplatelet therapy may not be warranted in patients with documented acquired von Willebrand syndrome, with or without extreme thrombocytosis, or in those in the very low-risk category according to the IPSET-thrombosis model.^55,87 The risk/benefit ratio of antiplatelet agents in patients with ET at different thrombotic risk levels was assessed in poor-quality studies and thus remains highly uncertain. Platelet-lowering agents are sometimes recommended in patients with low-risk disease who have platelet counts ≥ 1500 × 10³/µL, due to the potential risk of acquired von Willebrand syndrome and a risk of bleeding (this would require stopping ASA).¹⁰⁹ Cytoreduction may also be used in low-risk patients with progressive symptoms despite ASA, symptomatic or progressive splenomegaly, and progressive leukocytosis.

Intermediate-Risk ET

This category includes patients older than 60 years but without thrombosis or JAK2 mutations. These individuals would have been considered high risk (and thus candidates for cytoreductive therapy) according to the traditional risk stratification. Guidelines currently recommend ASA as the sole therapy for these patients, while reserving cytoreduction for those who experience thrombosis (ie, become high-risk) or have uncontrolled vasomotor or general symptoms, symptomatic splenomegaly, symptomatic thrombocytosis, or progressive leukocytosis.

High-Risk ET

For patients with ET in need of cytoreductive therapy (ie, those with prior thrombosis or older than 60 years with a JAK2V617F mutation), first-line options include hydroxyurea, IFN, and anagrelide. Hydroxyurea remains the treatment of choice in the majority of patients.¹¹⁰ In a seminal study, 114 patients with ET were randomly assigned to either observation or hydroxyurea treatment with the goal of maintaining the platelet count below 600 × 10³/µL. At a median follow-up of 27 months, patients in the hydroxyurea group had a lower thrombosis rate (3.6% versus 24%, P = 0.003) and longer thrombosis-free survival, regardless of the use of antiplatelet drugs.⁶⁴

Anagrelide, a selective inhibitor of megakaryocytic differentiation and proliferation, was compared with hydroxyurea in patients with ET in 2 randomized trials. In the first (N = 809), the group receiving anagrelide had a higher risk of arterial thrombosis, major bleeding, and fibrotic evolution, but lower incidence of venous thrombosis. Hydroxyurea was better tolerated, mainly due to anagrelide-related cardiovascular adverse events.¹¹¹ As a result of this study, hydroxyurea is often preferred to anagrelide as front-line therapy for patients with newly diagnosed high-risk ET. In the second, more recent study (N = 259), however, the 2 agents proved equivalent in terms of major or minor arterial or venous thrombosis, as well as discontinuation rate.¹¹² The discrepancy between the 2 trials may be partly explained by the different ET diagnostic criteria used, with the latter only enrolling patients with WHO-defined true ET, while the former utilized Polycythemia Vera Study Group-ET diagnostic criteria that included patients with increases in other blood counts or varying degrees of marrow fibrosis.

Interferons were studied in ET in parallel with PV. PEG-IFN alfa-2a proved effective in patients with ET, with responses observed in 80% of patients.¹⁰³ PEG-IFN alfa-2b produced similar results, with responses in 70% to 90% of patients in small studies and discontinuation observed in 20% to 38% of cases.^105,106,113 Because the very long-term leukemogenic potential of hydroxyurea has remained somewhat uncertain, anagrelide or IFN might be preferable choices in younger patients.

The approach to treatment of ET based on thrombotic risk level is illustrated in Figure 2.

Assessing Response to Therapy

For both patients with PV and ET the endpoint of treatment set forth for clinical trials has been the achievement of a clinicohematologic response. However, studies have failed to show a correlation between response and reduction of the thrombohemorrhagic risk.¹¹⁴ Therefore, proposed clinical trial response criteria were revised to include absence of hemorrhagic or thrombotic events as part of the definition of response (Table 3).⁹⁴

Cases Continued

Patient A was initially treated with phlebotomies and his blood counts were subsequently controlled with hydroxyurea, which he took uninterruptedly at an average dose of 2.5 g daily. He also took ASA daily throughout. Now, 18 months after the start of therapy, he presents with a complaint of fatigue for the past 3 months, which more recently has been associated with recurrent itching. A repeat CBC shows a WBC count of 17,200/µL, hemoglobin 181 g/L, and platelets 940 × 10³/µL.

Patient B presents for scheduled follow-up. She has had no further thrombotic episodes. However, she spontaneously discontinued hydroxyurea 1 month ago because of worsening mouth ulcers that impaired her ability to eat even small meals. She seeks recommendations for further treatment options.

Approach to Patients Refractory to or Intolerant of First-Line Therapy

According to the European LeukemiaNet recommendations, an inadequate response to hydroxyurea in patients with PV (or myelofibrosis) is defined as a need for phlebotomy to maintain hematocrit below < 45%, platelet count > 400 × 10³/µL, and a WBC count > 10,000/µL, or failure to reduce splenomegaly > 10 cm by > 50% at a dose of ≥ 2 g/day or maximum tolerated dose. Historically, treatment options for patients with PV or ET who failed first-line therapy (most commonly hydroxyurea) have included alkylating agents, such as busulfan, chlorambucil, or pipobroman, and phosphorus (P)-32. However, the use of these drugs is limited by the associated risk of leukemic transformation.^93,115,116 The use of IFN (or anagrelide for ET) is often considered in patients previously treated with hydroxyurea, and vice versa.

Ruxolitinib is a JAK1 and JAK2 inhibitor currently approved for the treatment of PV patients refractory to or intolerant of hydroxyurea.⁷ Following promising results of a phase 2 trial,¹¹⁷ ruxolitinib 10 mg twice daily was compared with best available therapy in the pivotal RESPONSE trial (N = 222). Ruxolitinib proved superior in achieving hematocrit control, reduction of spleen volume, and improvement of symptoms. Grade 3-4 hematologic toxicity was infrequent and similar in the 2 arms.¹¹⁸ In addition, longer follow-up of that study suggested a lower rate of thrombotic events in patients receiving ruxolitinib (1.8 versus 8.2 per 100 patient-years).¹¹⁹ In a similarly designed randomized phase 3 study in PV patients without splenomegaly (RESPONSE-2), more patients in the ruxolitinib arm had hematocrit reduction without an increase in toxicity. Based on the results of the above studies, ruxolitinib can be considered a standard of care for second-line therapy in this post-hydroxyurea patient population.¹²⁰

Ruxolitinib is also being tested in patients with high-risk ET who have become resistant to, or were intolerant of hydroxyurea, but currently has no approved indication in this setting.^121,122 Common side effects of ruxolitinib include cytopenias (especially anemia), increased risk of infections, hyperlipidemia, and increased risk of non-melanoma skin cancer.

Novel Agents

Novel agents that have been studied in patients with PV and ET are histone deacetylase inhibitors, murine double minute 2 (MDM2, or HDM2 for their human counterpart) inhibitors (which restore the function of p53), Bcl-2 homology domain 3 mimetics such as navitoclax and venetoclax, and, for patients with ET, the telomerase inhibitor imetelstat.¹²³

Disease Evolution

Cases Continued

Patient A’s PV has been well controlled with PEG-IFN alfa-2a 90 μg subcutaneously weekly. However, he now presents with a complaint of worsening fatigue and early satiety. On exam the patient appears ill and splenomegaly is appreciated 12 cm below the costal margin. CBC shows a WBC count of 2600/µL, hemoglobin 73 g/L, and platelets 122 × 10³/µL. Peripheral blood smear reveals leukoerythroblastosis and dacro­cytosis. CBC 6 months ago was normal. A bone marrow biopsy is consistent with myelofibrosis.

After discontinuing hydroxyurea, patient B’s ET has been well controlled with anagrelide. However, for the past 4 weeks she has complained of severe fatigue and easy bruising. Physical exam reveals a pale, ill-appearing woman with scattered bruises. CBC shows a WBC count of 14,600/µL with 44% myeloblasts, hemoglobin 73 g/L, and platelets 22 × 10³/µL. CBC 6 months ago was normal. A bone marrow biopsy is consistent with leukemic transformation of ET.

Post-PV/Post-ET Myelofibrosis

Diagnostic criteria for post-PV and post-ET myelofibrosis are outlined in Table 4.

Leukemic Transformation

The presence of more than 20% blasts in peripheral blood or bone marrow in a patient with MPN defines leukemic transformation. This occurs in up to 5% to 10% of patients and may or may not be preceded by a myelofibrosis phase.¹²⁶ In cases of extramedullary transformation, a lower percentage of blasts can be seen in the bone marrow compared to the peripheral blood. The pathogenesis of leukemic transformation has remained elusive, but it is believed to be associated with genetic instability, which facilitates the acquisition of additional mutations, including those of TET2, ASXL1, EZH2 and DNMT3, IDH1/2, and TP53.¹²⁷

Clinical risk factors for leukemic transformation include advanced age, karyotypic abnormalities, prior therapy with alkylating agents or P-32, splenectomy, increased peripheral blood or bone marrow blasts, leukocytosis, anemia, thrombocytopenia, and cytogenetic abnormalities. Hydroxyurea, interferon, and ruxolitinib have not been shown to have leukemogenic potential thus far. Prognosis of leukemic transformation is uniformly poor and patient survival rarely exceeds 6 months.

There is no standard of care for leukemic transformation of MPN (MPN-LT). Treatment options range from low-intensity regimens to more aggressive AML-type induction chemotherapy. No strategy appears clearly superior to others.¹²⁸ Hematopoietic stem cell transplantation is the only therapy that provides clinically meaningful benefit to patients,¹²⁹ but it is applicable only to a minority of patients with chemosensitive disease and good performance status.¹³⁰ Notable experimental approaches to MPN–LT include hypomethylating agents, such as decitabine¹³¹ or azacitidine,¹³² with or without ruxolitinib.^133-135

Conclusion

PV and ET are rare, chronic myeloid disorders. Patients typically experience a long clinical course and enjoy near-normal quality of life if properly managed. The 2 most important life-limiting complications of PV and ET are thrombohemorrhagic events and myelofibrosis/AML transformation. Vascular events are at least in part preventable with counseling on risk factors, phlebotomy (for patients with PV), antiplatelet therapy, and cytoreduction with hydroxyurea, IFNs, or anagrelide (for patients with ET). In addition, ruxolitinib was recently approved for PV patients after hydroxyurea failure. PV/ET transformation in myelofibrosis or AML is part of the natural history of the disease and no therapy has been shown to prevent it. Treatment follows recommendations set forth for PMF and AML, but results are generally poorer and novel strategies are needed to improve patients’ outcomes.

More than 80% of children who were given omalizumab with oral immunotherapy (OIT) for 36 weeks could safely consume portions of at least 2 foods they were causing an allergic reaction, according to findings from a phase 2 study funded by the National Institute of Allergy and Infectious Diseases. Omalizumab, an injectable antibody drug approved for moderate-to-severe allergic asthma, blocks the activity of IgE.

Researchers from Stanford University School of Medicine in California enrolled 48 children aged 4 years to 15 years with confirmed allergy to multiple foods, such as milk, egg, wheat, soy, sesame seeds, peanuts, and tree nuts. The children received omalizumab or placebo injections for the first 16 weeks. At week 8, all participants began eating small, gradually increasing amounts of an allergenic food. They continued OIT until week 36, when they underwent an oral food challenge.

Of the 36 children who received omalizumab, 30 were able to eat at least 2 grams of ≥ 2 allergenic foods, compared with that of only 4 of 12 children (33%) who received placebo. Children who received omalizumab also had fewer adverse events from OIT

More than 80% of children who were given omalizumab with oral immunotherapy (OIT) for 36 weeks could safely consume portions of at least 2 foods they were causing an allergic reaction, according to findings from a phase 2 study funded by the National Institute of Allergy and Infectious Diseases. Omalizumab, an injectable antibody drug approved for moderate-to-severe allergic asthma, blocks the activity of IgE.

Researchers from Stanford University School of Medicine in California enrolled 48 children aged 4 years to 15 years with confirmed allergy to multiple foods, such as milk, egg, wheat, soy, sesame seeds, peanuts, and tree nuts. The children received omalizumab or placebo injections for the first 16 weeks. At week 8, all participants began eating small, gradually increasing amounts of an allergenic food. They continued OIT until week 36, when they underwent an oral food challenge.

Of the 36 children who received omalizumab, 30 were able to eat at least 2 grams of ≥ 2 allergenic foods, compared with that of only 4 of 12 children (33%) who received placebo. Children who received omalizumab also had fewer adverse events from OIT

More than 80% of children who were given omalizumab with oral immunotherapy (OIT) for 36 weeks could safely consume portions of at least 2 foods they were causing an allergic reaction, according to findings from a phase 2 study funded by the National Institute of Allergy and Infectious Diseases. Omalizumab, an injectable antibody drug approved for moderate-to-severe allergic asthma, blocks the activity of IgE.

Researchers from Stanford University School of Medicine in California enrolled 48 children aged 4 years to 15 years with confirmed allergy to multiple foods, such as milk, egg, wheat, soy, sesame seeds, peanuts, and tree nuts. The children received omalizumab or placebo injections for the first 16 weeks. At week 8, all participants began eating small, gradually increasing amounts of an allergenic food. They continued OIT until week 36, when they underwent an oral food challenge.

Of the 36 children who received omalizumab, 30 were able to eat at least 2 grams of ≥ 2 allergenic foods, compared with that of only 4 of 12 children (33%) who received placebo. Children who received omalizumab also had fewer adverse events from OIT

Image by Tom Ellenberger

Researchers have used high-risk pedigrees (HRPs) to identify gene variants that may cause multiple myeloma (MM).

The team’s analysis revealed shared genomic segments harboring genes with potential MM risk variants.

These single nucleotide variants (SNVs) are in USP45, a gene involved in DNA repair, and ARID1A, a gene in the SWI/SNF chromatin remodeling complex.

Nicola Camp, PhD, of the University of Utah School of Medicine in Salt Lake City, and her colleagues reported these findings in PLOS Genetics.

The researchers developed a new method to analyze HRPs (large, multi-generational families with more affected members than would be expected by chance) to identify shared regions of the genome that likely harbor MM risk variants.

The team applied the method using pedigrees from 11 Utah families at risk of MM as well as whole-exome sequencing of shared genomic segments in 1063 patients with MM or monoclonal gammopathy of undetermined significance (MGUS) and 964 control subjects.

The analysis revealed 2 regions that may contribute to MM. One was a 1.8 Mb segment at 6q16 with SNVs in USP45, and the other was a 1.2 Mb segment at 1p36.11 with SNVs in ARID1A.

One of the SNVs in USP45 was a stop gain—p.Gln691*—which was shared by 3 siblings, 1 with MM and 2 with MGUS. The other was a missense SNV—p.Gln621Glu—which was shared by 2 of 4 siblings in a family, 1 with MM and 1 with MGUS.

One of the missense SNVs in ARID1A—rs752026201, p. Ser90Gly—was shared by 3 MM cases. The other missense SNV—rs140664170, p.Met890Val—was shared by 2 cousins with MM.

The researchers believe these findings show that HRPs can be effective for identifying risk variants in complex diseases.

“We are very encouraged by the new method,” Dr Camp said. “It certainly plays to the strengths of the large Utah pedigrees, revitalizing the family design for complex diseases. As we did in this study, the focused regions can be further investigated in smaller families to find genes and specific mutations. The method can be used for any complex disease.”

“We are already pursuing large pedigrees in several other domains, including other cancers, psychiatric disorders, birth defects, and pre-term birth phenotypes, with several more genome-wide significant regions found. We’re excited about the potential.”

Image by Tom Ellenberger

Researchers have used high-risk pedigrees (HRPs) to identify gene variants that may cause multiple myeloma (MM).

The team’s analysis revealed shared genomic segments harboring genes with potential MM risk variants.

These single nucleotide variants (SNVs) are in USP45, a gene involved in DNA repair, and ARID1A, a gene in the SWI/SNF chromatin remodeling complex.

Nicola Camp, PhD, of the University of Utah School of Medicine in Salt Lake City, and her colleagues reported these findings in PLOS Genetics.

The researchers developed a new method to analyze HRPs (large, multi-generational families with more affected members than would be expected by chance) to identify shared regions of the genome that likely harbor MM risk variants.

The team applied the method using pedigrees from 11 Utah families at risk of MM as well as whole-exome sequencing of shared genomic segments in 1063 patients with MM or monoclonal gammopathy of undetermined significance (MGUS) and 964 control subjects.

The analysis revealed 2 regions that may contribute to MM. One was a 1.8 Mb segment at 6q16 with SNVs in USP45, and the other was a 1.2 Mb segment at 1p36.11 with SNVs in ARID1A.

One of the SNVs in USP45 was a stop gain—p.Gln691*—which was shared by 3 siblings, 1 with MM and 2 with MGUS. The other was a missense SNV—p.Gln621Glu—which was shared by 2 of 4 siblings in a family, 1 with MM and 1 with MGUS.

One of the missense SNVs in ARID1A—rs752026201, p. Ser90Gly—was shared by 3 MM cases. The other missense SNV—rs140664170, p.Met890Val—was shared by 2 cousins with MM.

The researchers believe these findings show that HRPs can be effective for identifying risk variants in complex diseases.

“We are very encouraged by the new method,” Dr Camp said. “It certainly plays to the strengths of the large Utah pedigrees, revitalizing the family design for complex diseases. As we did in this study, the focused regions can be further investigated in smaller families to find genes and specific mutations. The method can be used for any complex disease.”

“We are already pursuing large pedigrees in several other domains, including other cancers, psychiatric disorders, birth defects, and pre-term birth phenotypes, with several more genome-wide significant regions found. We’re excited about the potential.”

Image by Tom Ellenberger

Researchers have used high-risk pedigrees (HRPs) to identify gene variants that may cause multiple myeloma (MM).

The team’s analysis revealed shared genomic segments harboring genes with potential MM risk variants.

These single nucleotide variants (SNVs) are in USP45, a gene involved in DNA repair, and ARID1A, a gene in the SWI/SNF chromatin remodeling complex.

Nicola Camp, PhD, of the University of Utah School of Medicine in Salt Lake City, and her colleagues reported these findings in PLOS Genetics.

The researchers developed a new method to analyze HRPs (large, multi-generational families with more affected members than would be expected by chance) to identify shared regions of the genome that likely harbor MM risk variants.

The team applied the method using pedigrees from 11 Utah families at risk of MM as well as whole-exome sequencing of shared genomic segments in 1063 patients with MM or monoclonal gammopathy of undetermined significance (MGUS) and 964 control subjects.

The analysis revealed 2 regions that may contribute to MM. One was a 1.8 Mb segment at 6q16 with SNVs in USP45, and the other was a 1.2 Mb segment at 1p36.11 with SNVs in ARID1A.

One of the SNVs in USP45 was a stop gain—p.Gln691*—which was shared by 3 siblings, 1 with MM and 2 with MGUS. The other was a missense SNV—p.Gln621Glu—which was shared by 2 of 4 siblings in a family, 1 with MM and 1 with MGUS.

One of the missense SNVs in ARID1A—rs752026201, p. Ser90Gly—was shared by 3 MM cases. The other missense SNV—rs140664170, p.Met890Val—was shared by 2 cousins with MM.

The researchers believe these findings show that HRPs can be effective for identifying risk variants in complex diseases.

“We are very encouraged by the new method,” Dr Camp said. “It certainly plays to the strengths of the large Utah pedigrees, revitalizing the family design for complex diseases. As we did in this study, the focused regions can be further investigated in smaller families to find genes and specific mutations. The method can be used for any complex disease.”

“We are already pursuing large pedigrees in several other domains, including other cancers, psychiatric disorders, birth defects, and pre-term birth phenotypes, with several more genome-wide significant regions found. We’re excited about the potential.”

Red and white blood cells

The US Food and Drug Administration (FDA) says it is evaluating reports of venous thromboembolism (VTE) in patients treated with the CELLEX Photopheresis System by Therakos, Inc.

This extracorporeal photopheresis (ECP) device system is FDA-approved for use in patients with cutaneous T-cell lymphoma (CTCL).

The system is used to perform ultraviolet-A irradiation of a patient’s own leukocyte-enriched blood that is then used as palliative treatment for skin manifestations of CTCL that are unresponsive to other forms of treatment.

The CELLEX Photopheresis System is also used to treat graft-vs-host disease (GVHD) that is resistant to standard immunosuppressive therapy and acute cardiac allograft rejection that is resistant to standard immunosuppressive therapy.

The CELLEX Photopheresis System uses methoxsalen as a photosensitizing agent and heparin as an anticoagulant.

Since 2012, the FDA has received 7 reports of pulmonary embolism (PE) and 2 reports of deep vein thrombosis (DVT) occurring during or soon after treatment with the CELLEX Photopheresis System.

Two of the patients who developed a PE died, although it’s not clear whether PE was the cause of death.

Four of the 7 PEs occurred in patients undergoing treatment for GVHD, including the 2 patients who died. Both DVTs occurred in patients undergoing treatment for GVHD as well.

The FDA is recommending that healthcare providers inform patients, clinical staff, and technicians that PE and DVT can occur during or after an ECP procedure.

The agency also recommends that healthcare providers consult device labeling regarding anticoagulation and use clinical judgment in adjusting a patient’s heparin dosage.

Finally, providers should report VTEs related to ECP procedures to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.

If possible, reports should include the following:

• The indication for ECP therapy
• Comorbidities that may predispose a patient to increased coagulation and history of DVT or PE
• The anticoagulation regimen used
• The number of ECP sessions the patient underwent prior to VTE onset, including the date of the first treatment session, frequency of treatment sessions, and timing of the final treatment
• Timing of the VTE in relation to the most recent treatment session
• Interventions required to manage the VTE.
  

Red and white blood cells

The US Food and Drug Administration (FDA) says it is evaluating reports of venous thromboembolism (VTE) in patients treated with the CELLEX Photopheresis System by Therakos, Inc.

This extracorporeal photopheresis (ECP) device system is FDA-approved for use in patients with cutaneous T-cell lymphoma (CTCL).

The system is used to perform ultraviolet-A irradiation of a patient’s own leukocyte-enriched blood that is then used as palliative treatment for skin manifestations of CTCL that are unresponsive to other forms of treatment.

The CELLEX Photopheresis System is also used to treat graft-vs-host disease (GVHD) that is resistant to standard immunosuppressive therapy and acute cardiac allograft rejection that is resistant to standard immunosuppressive therapy.

The CELLEX Photopheresis System uses methoxsalen as a photosensitizing agent and heparin as an anticoagulant.

Since 2012, the FDA has received 7 reports of pulmonary embolism (PE) and 2 reports of deep vein thrombosis (DVT) occurring during or soon after treatment with the CELLEX Photopheresis System.

Two of the patients who developed a PE died, although it’s not clear whether PE was the cause of death.

Four of the 7 PEs occurred in patients undergoing treatment for GVHD, including the 2 patients who died. Both DVTs occurred in patients undergoing treatment for GVHD as well.

The FDA is recommending that healthcare providers inform patients, clinical staff, and technicians that PE and DVT can occur during or after an ECP procedure.

The agency also recommends that healthcare providers consult device labeling regarding anticoagulation and use clinical judgment in adjusting a patient’s heparin dosage.

Finally, providers should report VTEs related to ECP procedures to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.

If possible, reports should include the following:

• The indication for ECP therapy
• Comorbidities that may predispose a patient to increased coagulation and history of DVT or PE
• The anticoagulation regimen used
• The number of ECP sessions the patient underwent prior to VTE onset, including the date of the first treatment session, frequency of treatment sessions, and timing of the final treatment
• Timing of the VTE in relation to the most recent treatment session
• Interventions required to manage the VTE.
  

Red and white blood cells

The US Food and Drug Administration (FDA) says it is evaluating reports of venous thromboembolism (VTE) in patients treated with the CELLEX Photopheresis System by Therakos, Inc.

This extracorporeal photopheresis (ECP) device system is FDA-approved for use in patients with cutaneous T-cell lymphoma (CTCL).

The system is used to perform ultraviolet-A irradiation of a patient’s own leukocyte-enriched blood that is then used as palliative treatment for skin manifestations of CTCL that are unresponsive to other forms of treatment.

The CELLEX Photopheresis System is also used to treat graft-vs-host disease (GVHD) that is resistant to standard immunosuppressive therapy and acute cardiac allograft rejection that is resistant to standard immunosuppressive therapy.

The CELLEX Photopheresis System uses methoxsalen as a photosensitizing agent and heparin as an anticoagulant.

Since 2012, the FDA has received 7 reports of pulmonary embolism (PE) and 2 reports of deep vein thrombosis (DVT) occurring during or soon after treatment with the CELLEX Photopheresis System.

Two of the patients who developed a PE died, although it’s not clear whether PE was the cause of death.

Four of the 7 PEs occurred in patients undergoing treatment for GVHD, including the 2 patients who died. Both DVTs occurred in patients undergoing treatment for GVHD as well.

The FDA is recommending that healthcare providers inform patients, clinical staff, and technicians that PE and DVT can occur during or after an ECP procedure.

The agency also recommends that healthcare providers consult device labeling regarding anticoagulation and use clinical judgment in adjusting a patient’s heparin dosage.

Finally, providers should report VTEs related to ECP procedures to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.

If possible, reports should include the following:

• The indication for ECP therapy
• Comorbidities that may predispose a patient to increased coagulation and history of DVT or PE
• The anticoagulation regimen used
• The number of ECP sessions the patient underwent prior to VTE onset, including the date of the first treatment session, frequency of treatment sessions, and timing of the final treatment
• Timing of the VTE in relation to the most recent treatment session
• Interventions required to manage the VTE.
  

The surfaces of the human body exposed to the environment are colonized by microbes—the majority of which reside in the intestinal tract. Collectively, the microbial cells that live in and on us (bacteria, eukaryotes, viruses, fungi, and archaea) make up our microbiota, and their genetic material constitutes our microbiome. There are at least 100 times more genes in the human microbiome than in the human genome.^1,2

With the help of recent technologic advances in genetic sequencing, we’re beginning to understand more about this vast biological habitat. We know that the microbiota plays a role in vitamin production, energy harvest and storage, and fermentation and absorption of undigested carbohydrates. It also has bidirectional influence on the central nervous system and neuropsychologic health and is involved in the maturation and development of the immune system.

A healthy biome is characterized by bacterial diversity and richness. Gut microbiota is mostly comprised of Firmicutes (64%), Bacteroidetes (23%), Proteobacteria (8%), and Actinobacteria (3%).² The distribution of these bacteria is largely determined by diet; individuals who follow a diet high in animal fat have a Bacteroides-dominant pattern, whereas those who follow a carbohydrate-rich diet tend toward a Prevotella-dominant pattern.^1-3

Lack of bacterial diversity and overgrowth of pathobacteria results in dysbiosis, an imbalance in the gut’s microbial composition. Alterations in the proportions of bacteria are thought to result in metabolic disease. As such, dysbiosis is correlated with obesity and diabetes, as well as other diseases (eg, inflammatory bowel disease, multiple sclerosis, Crohn disease, and rheumatoid arthritis).^1-3 At this time, however, it is unclear whether these bacterial imbalances cause or result from disease.

ROLE IN TYPE 2 DIABETES

The microbiome of patients with type 2 diabetes (T2DM) is characterized by reduced levels of Firmicutes and Clostridia and an increased ratio of Bacteroidetes:Firmicutes (this ratio correlates with plasma glucose concentration).^4,5 Interestingly, although T2DM and obesity are closely related, available data indicate that gut microbiome changes are not always identical between these two patient populations. In some studies, the microbiome of obese individuals involves a decreased Bacteroidetes:Firmicutes ratio, in contrast to the increase seen with T2DM—which raises the question of whether the same or different factors cause these two entities.^1,5-7

Patients with T2DM also have decreased amounts of butyrate-producing bacteria in their microbiomes. Butyrate, acetate, and propionate are short-chain fatty acids (­SCFAs) fermented in the large intestine by bacteria from dietary fiber. These SCFAs play an important role in energy metabolism and are critical for modulating immune responses and tumorigenesis in the gut. Butyrate, in particular, provides energy for colonic epithelial cells. By feeding colonic cells, butyrate helps to maintain intestinal integrity and prevent translocation—a process that moves gram-negative intestinal bacteria across the lumen of the gut, causing endotoxemia. Endotoxemia triggers a low-grade inflammatory response, and low-grade inflammation is thought to underlie T2DM.^2,5,6

Therapeutic interventions—such as dietary modifications, prebiotics, probiotics, antibiotics, metformin, fecal transplantation, and bariatric surgery—can effectively alter the composition of gut bacteria. It has been proposed that these interventions could be harnessed to prevent and treat T2DM in the future.² So, what might these interventions have (or not have) to offer?

ANTIBIOTICS

Antibiotics are useful for eradicating pathogenic bacteria, but they can also destroy beneficial intestinal commensals in the process. Therefore, concern about the widespread use of antibiotics in humans and livestock has increased. Subtherapeutic use of antibiotics, which has been common in farm animals throughout the past 50 years to increase growth and food production, has been shown to affect metabolic pathways—particularly with respect to SCFAs—in mouse studies.⁶

Recent data on humans have linked antibiotic treatment in early infancy to long-term effects on microbial diversity and childhood overweight. Similarly, long-term use of IV vancomycin in adults has been linked to an increased obesity risk. But it’s not just long-term exposure that poses a threat; even short courses of oral antibiotics can have profound and irreversible ­effects on intestinal microbial diversity and composition. For example, short-term use of oral vancomycin was found to impair peripheral insulin sensitivity in males with metabolic syndrome associated with ­altered gut microbiota, while amoxicillin did not.⁶

PREBIOTICS AND PROBIOTICS

Prebiotics are indigestible carbohydrates that improve host health by stimulating the growth and activity of colonic bacteria. Most prebiotics are oligosaccharides, which can travel through the upper GI system undigested. When they reach the colon, they are fermented to produce SCFAs that stimulate the growth of microbes that reside there. Prebiotics come from a wide variety of food sources, including asparagus, barley, garlic, onions, and wheat bran.^2,3 Pickled and fermented foods (eg, kimchi, sauerkraut, yogurt, miso) are good sources of both prebiotics and probiotics.²

Bifidobacteria and lactobacilli are the most commonly used strains in foods and supplements containing probiotics. These live microorganisms bring about specific changes in the composition and activity of gut microbiota: they secrete antimicrobial substances, compete with pathogenic bacteria, strengthen the intestinal barrier, and modulate the immune system.^2,3,6 Research on human and animal models suggests that administering probiotics may help manage diabetes.²

DIETARY MODULATION

Dietary changes have been shown to modify the bacterial metabolic activity of the human gut. In one study, obese adults with T2DM were placed on either a fat- or carbohydrate-restricted diet, and it was found that their levels of Bacteroidetes increased and Firmicutes decreased.⁷

In another study, patients with T2DM adhered to one of two calorie-controlled diets: a high-fiber macrobiotic diet or a Mediterranean-style (control) diet. The macrobiotic diet was high in complex carbohydrates, legumes, fermented products, sea salt, and green tea and was free of animal protein, fat, and added sugar. Both diets were effective at improving dysbiosis—ecosystem diversity increased, and health-promoting SCFA producers were replenished. However, the macrobiotic diet was more effective than the control diet at reducing fasting and postprandial glucose, A1C, serum cholesterol, insulin resistance, BMI, and waist and hip circumferences; and only the macrobiotic diet counteracted the inflammation-producing bacterial groups.⁸

METFORMIN

Metformin has therapeutic effects on microbial composition and SCFA synthesis. In a microbiome comparison study, patients with T2DM treated with metformin had more butyrate-producing bacteria than their untreated counterparts. The trend toward increased Lactobacillus seen in the context of T2DM was reduced or reversed by metformin treatment. Researchers were able to tell which patients were (and were not) treated based on their gut microbiome taxonomic signature.⁹

FECAL MICROBIOTA TRANSPLANT

Fecal microbiota transplant, also known as stool transplant or bacteriotherapy, is the process of transferring fecal bacteria from a healthy individual into a recipient. It is used in the treatment of recurrent Clostridium difficile colitis to replenish beneficial bacteria in the digestive tract following use of wide-spectrum antibiotics. In a double-blind randomized controlled trial, insulin-resistant men received either autologous (reinfusion of one’s collected feces) or allogenic (feces from a lean donor) infusions. Allogenic transplantation resulted in significantly increased intestinal microbial diversity and increased levels of butyrate-producing species, accompanied by significantly improved peripheral muscle sensitivity to insulin.^1,6

BARIATRIC SURGERY

Bariatric surgery, specifically Roux-en-Y gastric bypass (RYGBP), is a powerful tool used to treat obesity. In six patients (five of whom had diabetes) treated with RYGBP, dramatic changes to the gut microbiota were seen at three months following surgery. BMI was reduced by 15% to 32%, C-reactive protein decreased in five of six patients, and T2DM was alleviated in all. Postoperatively, there was a striking shift towards higher amounts of Proteobacteria and lower relative amounts of Firmicutes and Bacteroides in the gut phyla. Postoperative increases in certain bacteria were more profound than the amount in lean controls, suggesting these changes are related to alterations in the gut, not lower body weight.^4,6

CONCLUSION

We are just beginning to understand the microbiome and its relationship to health and disease. For patients with T2DM, a variety of interventions may be used to return the gut microbiota to health. Dietary interventions, prebiotics and probiotics, fecal microbial transplant, and bariatric surgery can influence gut microbial composition, with the goal of preventing and/or treating disease. In the future, gut microbial signatures may serve as early diagnostic markers.

The surfaces of the human body exposed to the environment are colonized by microbes—the majority of which reside in the intestinal tract. Collectively, the microbial cells that live in and on us (bacteria, eukaryotes, viruses, fungi, and archaea) make up our microbiota, and their genetic material constitutes our microbiome. There are at least 100 times more genes in the human microbiome than in the human genome.^1,2

With the help of recent technologic advances in genetic sequencing, we’re beginning to understand more about this vast biological habitat. We know that the microbiota plays a role in vitamin production, energy harvest and storage, and fermentation and absorption of undigested carbohydrates. It also has bidirectional influence on the central nervous system and neuropsychologic health and is involved in the maturation and development of the immune system.

A healthy biome is characterized by bacterial diversity and richness. Gut microbiota is mostly comprised of Firmicutes (64%), Bacteroidetes (23%), Proteobacteria (8%), and Actinobacteria (3%).² The distribution of these bacteria is largely determined by diet; individuals who follow a diet high in animal fat have a Bacteroides-dominant pattern, whereas those who follow a carbohydrate-rich diet tend toward a Prevotella-dominant pattern.^1-3

Lack of bacterial diversity and overgrowth of pathobacteria results in dysbiosis, an imbalance in the gut’s microbial composition. Alterations in the proportions of bacteria are thought to result in metabolic disease. As such, dysbiosis is correlated with obesity and diabetes, as well as other diseases (eg, inflammatory bowel disease, multiple sclerosis, Crohn disease, and rheumatoid arthritis).^1-3 At this time, however, it is unclear whether these bacterial imbalances cause or result from disease.

ROLE IN TYPE 2 DIABETES

The microbiome of patients with type 2 diabetes (T2DM) is characterized by reduced levels of Firmicutes and Clostridia and an increased ratio of Bacteroidetes:Firmicutes (this ratio correlates with plasma glucose concentration).^4,5 Interestingly, although T2DM and obesity are closely related, available data indicate that gut microbiome changes are not always identical between these two patient populations. In some studies, the microbiome of obese individuals involves a decreased Bacteroidetes:Firmicutes ratio, in contrast to the increase seen with T2DM—which raises the question of whether the same or different factors cause these two entities.^1,5-7

Patients with T2DM also have decreased amounts of butyrate-producing bacteria in their microbiomes. Butyrate, acetate, and propionate are short-chain fatty acids (­SCFAs) fermented in the large intestine by bacteria from dietary fiber. These SCFAs play an important role in energy metabolism and are critical for modulating immune responses and tumorigenesis in the gut. Butyrate, in particular, provides energy for colonic epithelial cells. By feeding colonic cells, butyrate helps to maintain intestinal integrity and prevent translocation—a process that moves gram-negative intestinal bacteria across the lumen of the gut, causing endotoxemia. Endotoxemia triggers a low-grade inflammatory response, and low-grade inflammation is thought to underlie T2DM.^2,5,6

Therapeutic interventions—such as dietary modifications, prebiotics, probiotics, antibiotics, metformin, fecal transplantation, and bariatric surgery—can effectively alter the composition of gut bacteria. It has been proposed that these interventions could be harnessed to prevent and treat T2DM in the future.² So, what might these interventions have (or not have) to offer?

ANTIBIOTICS

Antibiotics are useful for eradicating pathogenic bacteria, but they can also destroy beneficial intestinal commensals in the process. Therefore, concern about the widespread use of antibiotics in humans and livestock has increased. Subtherapeutic use of antibiotics, which has been common in farm animals throughout the past 50 years to increase growth and food production, has been shown to affect metabolic pathways—particularly with respect to SCFAs—in mouse studies.⁶

Recent data on humans have linked antibiotic treatment in early infancy to long-term effects on microbial diversity and childhood overweight. Similarly, long-term use of IV vancomycin in adults has been linked to an increased obesity risk. But it’s not just long-term exposure that poses a threat; even short courses of oral antibiotics can have profound and irreversible ­effects on intestinal microbial diversity and composition. For example, short-term use of oral vancomycin was found to impair peripheral insulin sensitivity in males with metabolic syndrome associated with ­altered gut microbiota, while amoxicillin did not.⁶

PREBIOTICS AND PROBIOTICS

Prebiotics are indigestible carbohydrates that improve host health by stimulating the growth and activity of colonic bacteria. Most prebiotics are oligosaccharides, which can travel through the upper GI system undigested. When they reach the colon, they are fermented to produce SCFAs that stimulate the growth of microbes that reside there. Prebiotics come from a wide variety of food sources, including asparagus, barley, garlic, onions, and wheat bran.^2,3 Pickled and fermented foods (eg, kimchi, sauerkraut, yogurt, miso) are good sources of both prebiotics and probiotics.²

Bifidobacteria and lactobacilli are the most commonly used strains in foods and supplements containing probiotics. These live microorganisms bring about specific changes in the composition and activity of gut microbiota: they secrete antimicrobial substances, compete with pathogenic bacteria, strengthen the intestinal barrier, and modulate the immune system.^2,3,6 Research on human and animal models suggests that administering probiotics may help manage diabetes.²

DIETARY MODULATION

Dietary changes have been shown to modify the bacterial metabolic activity of the human gut. In one study, obese adults with T2DM were placed on either a fat- or carbohydrate-restricted diet, and it was found that their levels of Bacteroidetes increased and Firmicutes decreased.⁷

In another study, patients with T2DM adhered to one of two calorie-controlled diets: a high-fiber macrobiotic diet or a Mediterranean-style (control) diet. The macrobiotic diet was high in complex carbohydrates, legumes, fermented products, sea salt, and green tea and was free of animal protein, fat, and added sugar. Both diets were effective at improving dysbiosis—ecosystem diversity increased, and health-promoting SCFA producers were replenished. However, the macrobiotic diet was more effective than the control diet at reducing fasting and postprandial glucose, A1C, serum cholesterol, insulin resistance, BMI, and waist and hip circumferences; and only the macrobiotic diet counteracted the inflammation-producing bacterial groups.⁸

METFORMIN

Metformin has therapeutic effects on microbial composition and SCFA synthesis. In a microbiome comparison study, patients with T2DM treated with metformin had more butyrate-producing bacteria than their untreated counterparts. The trend toward increased Lactobacillus seen in the context of T2DM was reduced or reversed by metformin treatment. Researchers were able to tell which patients were (and were not) treated based on their gut microbiome taxonomic signature.⁹

FECAL MICROBIOTA TRANSPLANT

Fecal microbiota transplant, also known as stool transplant or bacteriotherapy, is the process of transferring fecal bacteria from a healthy individual into a recipient. It is used in the treatment of recurrent Clostridium difficile colitis to replenish beneficial bacteria in the digestive tract following use of wide-spectrum antibiotics. In a double-blind randomized controlled trial, insulin-resistant men received either autologous (reinfusion of one’s collected feces) or allogenic (feces from a lean donor) infusions. Allogenic transplantation resulted in significantly increased intestinal microbial diversity and increased levels of butyrate-producing species, accompanied by significantly improved peripheral muscle sensitivity to insulin.^1,6

BARIATRIC SURGERY

Bariatric surgery, specifically Roux-en-Y gastric bypass (RYGBP), is a powerful tool used to treat obesity. In six patients (five of whom had diabetes) treated with RYGBP, dramatic changes to the gut microbiota were seen at three months following surgery. BMI was reduced by 15% to 32%, C-reactive protein decreased in five of six patients, and T2DM was alleviated in all. Postoperatively, there was a striking shift towards higher amounts of Proteobacteria and lower relative amounts of Firmicutes and Bacteroides in the gut phyla. Postoperative increases in certain bacteria were more profound than the amount in lean controls, suggesting these changes are related to alterations in the gut, not lower body weight.^4,6

CONCLUSION

We are just beginning to understand the microbiome and its relationship to health and disease. For patients with T2DM, a variety of interventions may be used to return the gut microbiota to health. Dietary interventions, prebiotics and probiotics, fecal microbial transplant, and bariatric surgery can influence gut microbial composition, with the goal of preventing and/or treating disease. In the future, gut microbial signatures may serve as early diagnostic markers.

The surfaces of the human body exposed to the environment are colonized by microbes—the majority of which reside in the intestinal tract. Collectively, the microbial cells that live in and on us (bacteria, eukaryotes, viruses, fungi, and archaea) make up our microbiota, and their genetic material constitutes our microbiome. There are at least 100 times more genes in the human microbiome than in the human genome.^1,2

With the help of recent technologic advances in genetic sequencing, we’re beginning to understand more about this vast biological habitat. We know that the microbiota plays a role in vitamin production, energy harvest and storage, and fermentation and absorption of undigested carbohydrates. It also has bidirectional influence on the central nervous system and neuropsychologic health and is involved in the maturation and development of the immune system.

A healthy biome is characterized by bacterial diversity and richness. Gut microbiota is mostly comprised of Firmicutes (64%), Bacteroidetes (23%), Proteobacteria (8%), and Actinobacteria (3%).² The distribution of these bacteria is largely determined by diet; individuals who follow a diet high in animal fat have a Bacteroides-dominant pattern, whereas those who follow a carbohydrate-rich diet tend toward a Prevotella-dominant pattern.^1-3

Lack of bacterial diversity and overgrowth of pathobacteria results in dysbiosis, an imbalance in the gut’s microbial composition. Alterations in the proportions of bacteria are thought to result in metabolic disease. As such, dysbiosis is correlated with obesity and diabetes, as well as other diseases (eg, inflammatory bowel disease, multiple sclerosis, Crohn disease, and rheumatoid arthritis).^1-3 At this time, however, it is unclear whether these bacterial imbalances cause or result from disease.

ROLE IN TYPE 2 DIABETES

The microbiome of patients with type 2 diabetes (T2DM) is characterized by reduced levels of Firmicutes and Clostridia and an increased ratio of Bacteroidetes:Firmicutes (this ratio correlates with plasma glucose concentration).^4,5 Interestingly, although T2DM and obesity are closely related, available data indicate that gut microbiome changes are not always identical between these two patient populations. In some studies, the microbiome of obese individuals involves a decreased Bacteroidetes:Firmicutes ratio, in contrast to the increase seen with T2DM—which raises the question of whether the same or different factors cause these two entities.^1,5-7

Patients with T2DM also have decreased amounts of butyrate-producing bacteria in their microbiomes. Butyrate, acetate, and propionate are short-chain fatty acids (­SCFAs) fermented in the large intestine by bacteria from dietary fiber. These SCFAs play an important role in energy metabolism and are critical for modulating immune responses and tumorigenesis in the gut. Butyrate, in particular, provides energy for colonic epithelial cells. By feeding colonic cells, butyrate helps to maintain intestinal integrity and prevent translocation—a process that moves gram-negative intestinal bacteria across the lumen of the gut, causing endotoxemia. Endotoxemia triggers a low-grade inflammatory response, and low-grade inflammation is thought to underlie T2DM.^2,5,6

Therapeutic interventions—such as dietary modifications, prebiotics, probiotics, antibiotics, metformin, fecal transplantation, and bariatric surgery—can effectively alter the composition of gut bacteria. It has been proposed that these interventions could be harnessed to prevent and treat T2DM in the future.² So, what might these interventions have (or not have) to offer?

ANTIBIOTICS

Antibiotics are useful for eradicating pathogenic bacteria, but they can also destroy beneficial intestinal commensals in the process. Therefore, concern about the widespread use of antibiotics in humans and livestock has increased. Subtherapeutic use of antibiotics, which has been common in farm animals throughout the past 50 years to increase growth and food production, has been shown to affect metabolic pathways—particularly with respect to SCFAs—in mouse studies.⁶

Recent data on humans have linked antibiotic treatment in early infancy to long-term effects on microbial diversity and childhood overweight. Similarly, long-term use of IV vancomycin in adults has been linked to an increased obesity risk. But it’s not just long-term exposure that poses a threat; even short courses of oral antibiotics can have profound and irreversible ­effects on intestinal microbial diversity and composition. For example, short-term use of oral vancomycin was found to impair peripheral insulin sensitivity in males with metabolic syndrome associated with ­altered gut microbiota, while amoxicillin did not.⁶

PREBIOTICS AND PROBIOTICS

Prebiotics are indigestible carbohydrates that improve host health by stimulating the growth and activity of colonic bacteria. Most prebiotics are oligosaccharides, which can travel through the upper GI system undigested. When they reach the colon, they are fermented to produce SCFAs that stimulate the growth of microbes that reside there. Prebiotics come from a wide variety of food sources, including asparagus, barley, garlic, onions, and wheat bran.^2,3 Pickled and fermented foods (eg, kimchi, sauerkraut, yogurt, miso) are good sources of both prebiotics and probiotics.²

Bifidobacteria and lactobacilli are the most commonly used strains in foods and supplements containing probiotics. These live microorganisms bring about specific changes in the composition and activity of gut microbiota: they secrete antimicrobial substances, compete with pathogenic bacteria, strengthen the intestinal barrier, and modulate the immune system.^2,3,6 Research on human and animal models suggests that administering probiotics may help manage diabetes.²

DIETARY MODULATION

Dietary changes have been shown to modify the bacterial metabolic activity of the human gut. In one study, obese adults with T2DM were placed on either a fat- or carbohydrate-restricted diet, and it was found that their levels of Bacteroidetes increased and Firmicutes decreased.⁷

In another study, patients with T2DM adhered to one of two calorie-controlled diets: a high-fiber macrobiotic diet or a Mediterranean-style (control) diet. The macrobiotic diet was high in complex carbohydrates, legumes, fermented products, sea salt, and green tea and was free of animal protein, fat, and added sugar. Both diets were effective at improving dysbiosis—ecosystem diversity increased, and health-promoting SCFA producers were replenished. However, the macrobiotic diet was more effective than the control diet at reducing fasting and postprandial glucose, A1C, serum cholesterol, insulin resistance, BMI, and waist and hip circumferences; and only the macrobiotic diet counteracted the inflammation-producing bacterial groups.⁸

METFORMIN

Metformin has therapeutic effects on microbial composition and SCFA synthesis. In a microbiome comparison study, patients with T2DM treated with metformin had more butyrate-producing bacteria than their untreated counterparts. The trend toward increased Lactobacillus seen in the context of T2DM was reduced or reversed by metformin treatment. Researchers were able to tell which patients were (and were not) treated based on their gut microbiome taxonomic signature.⁹

FECAL MICROBIOTA TRANSPLANT

Fecal microbiota transplant, also known as stool transplant or bacteriotherapy, is the process of transferring fecal bacteria from a healthy individual into a recipient. It is used in the treatment of recurrent Clostridium difficile colitis to replenish beneficial bacteria in the digestive tract following use of wide-spectrum antibiotics. In a double-blind randomized controlled trial, insulin-resistant men received either autologous (reinfusion of one’s collected feces) or allogenic (feces from a lean donor) infusions. Allogenic transplantation resulted in significantly increased intestinal microbial diversity and increased levels of butyrate-producing species, accompanied by significantly improved peripheral muscle sensitivity to insulin.^1,6

BARIATRIC SURGERY

Bariatric surgery, specifically Roux-en-Y gastric bypass (RYGBP), is a powerful tool used to treat obesity. In six patients (five of whom had diabetes) treated with RYGBP, dramatic changes to the gut microbiota were seen at three months following surgery. BMI was reduced by 15% to 32%, C-reactive protein decreased in five of six patients, and T2DM was alleviated in all. Postoperatively, there was a striking shift towards higher amounts of Proteobacteria and lower relative amounts of Firmicutes and Bacteroides in the gut phyla. Postoperative increases in certain bacteria were more profound than the amount in lean controls, suggesting these changes are related to alterations in the gut, not lower body weight.^4,6

CONCLUSION

We are just beginning to understand the microbiome and its relationship to health and disease. For patients with T2DM, a variety of interventions may be used to return the gut microbiota to health. Dietary interventions, prebiotics and probiotics, fecal microbial transplant, and bariatric surgery can influence gut microbial composition, with the goal of preventing and/or treating disease. In the future, gut microbial signatures may serve as early diagnostic markers.

KAUAI, HAWAII – Two keys to effective topical treatment of onychomycosis are treat it early and address coexisting tinea pedis, according to Theodore Rosen, MD.

A third element in achieving treatment success is to use one of the newer topical agents: efinaconazole (Jublia) or tavaborole (Kerydin). The efficacy of efinaconazole approaches that of terbinafine, the most effective and widely prescribed oral agent, which has a 59% rate of almost complete cure, defined as less than 10% residual abnormal nail with no requirement for mycologic cure.

Bruce Jancin/Frontline Medical News

And while tavaborole isn’t quite as effective, it’s definitely better than previous topical agents, Dr. Rosen said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

Both of these topicals are well tolerated and feature good nail permeation. They also allow for spread to the lateral nail folds and hyponychium. They even penetrate nail polish, although efinaconazole often causes the polish to lose its spiffy gloss, said Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston.

To underscore the importance of early treatment and addressing concomitant tinea pedis, he cited published secondary analyses of two identical double-blind, multicenter, 48-week clinical trials totaling 1,655 adults with onychomycosis who were randomized 3:1 to once-daily efinaconazole 10% topical solution or its vehicle.
 

Treat early

Phoebe Rich, MD, of the Oregon Dermatology and Research Center, Portland, broke down the outcomes according to disease duration, in a study of more than 1,500 patients with onychomycosis. She found that the complete cure rate at 52 weeks dropped off markedly in patients with a history of onychomycosis for 1 year or longer at baseline.

Complete cure – defined as no clinical involvement of the target toenail along with both a negative potassium hydroxide examination and a negative fungal culture at 52 weeks – was achieved in 43% of efinaconazole-treated patients with onychomycosis for less than 1 year. The rate then plunged to 17% in those with a disease duration of 1-5 years and 16% in patients with onychomycosis for more than 5 years. Nevertheless, the topical antifungal was significantly more effective than was the vehicle, across the board, with complete cure rates in the vehicle group of roughly 18%, 5%, and 2%, respectively, in patients with onychomycosis for less than 1 year, 1-5 years, and more than 5 years (J Drugs Dermatol. 2015 Jan;14[1]:58-62).
 

Tackle coexisting tinea pedis

Podiatrists analyzed the combined efinaconazole outcome data based on whether participants had no coexisting tinea pedis, baseline tinea pedis treated concomitantly with an investigator-approved topical antifungal, or tinea pedis left untreated. They concluded that treatment of coexisting tinea pedis decisively enhanced the efficacy of efinaconazole for onychomycosis.

A total of 21% of study participants had concomitant tinea pedis, and 61% of them were treated for it. At week 52, the onychomycosis complete cure rate was 29% in the efinaconazole group concurrently treated for tinea pedis, compared with just 16% if their tinea pedis was untreated (J Am Podiatr Med Assoc. 2015 Sep;105[5]:407-11).

“If you see tinea pedis, don’t blow it off. Treat it. Otherwise, you’re not getting rid of the fungal reservoir,” Dr. Rosen emphasized.

He noted that two topical agents approved for tinea pedis – naftifine 2% cream or gel and luliconazole 1% cream – are effective as once-daily therapy for 2 weeks, a considerably briefer regimen than with other approved topicals. And short-course therapy spells improved adherence, he added.

In the pivotal trials, naftifine had an effective treatment rate – a clinically useful endpoint defined as a small amount of residual scaling and/or redness but no itching – of 57%, while for luliconazole the rates were 33%-48%.

These two agents also are approved for treatment of tinea corporis and tinea cruris. Naftifine is approved as a once-daily treatment for 2 weeks, while luliconazole is, notably, a 7-day treatment. Luliconazole, in particular, is a relatively expensive drug, Dr. Rosen added, so insurers may require prior failure on clotrimazole.
 

When to treat onychomycosis topically

The pivotal trials of tavaborole and efinaconazole were conducted in patients with 20%-60% nail involvement. The infection didn’t extend to the matrix, and nail thickness and crumbly subungual debris were modest at baseline.

“There are always potential safety issues – drug interactions, GI disturbance, taste loss, headache, teratogenicity, cardiotoxicity, hepatotoxicity – anytime you put a pill in your mouth. So if you have a patient who’s dedicated enough to use a topical for 48 weeks and it’s a modestly affected nail, think about it,” Dr. Rosen advised.

He reported serving on scientific advisory boards for Aclaris, Anacor, Cipla, and Valeant.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
 

[email protected]

KAUAI, HAWAII – Two keys to effective topical treatment of onychomycosis are treat it early and address coexisting tinea pedis, according to Theodore Rosen, MD.

A third element in achieving treatment success is to use one of the newer topical agents: efinaconazole (Jublia) or tavaborole (Kerydin). The efficacy of efinaconazole approaches that of terbinafine, the most effective and widely prescribed oral agent, which has a 59% rate of almost complete cure, defined as less than 10% residual abnormal nail with no requirement for mycologic cure.

Bruce Jancin/Frontline Medical News

And while tavaborole isn’t quite as effective, it’s definitely better than previous topical agents, Dr. Rosen said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

Both of these topicals are well tolerated and feature good nail permeation. They also allow for spread to the lateral nail folds and hyponychium. They even penetrate nail polish, although efinaconazole often causes the polish to lose its spiffy gloss, said Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston.

To underscore the importance of early treatment and addressing concomitant tinea pedis, he cited published secondary analyses of two identical double-blind, multicenter, 48-week clinical trials totaling 1,655 adults with onychomycosis who were randomized 3:1 to once-daily efinaconazole 10% topical solution or its vehicle.
 

Treat early

Phoebe Rich, MD, of the Oregon Dermatology and Research Center, Portland, broke down the outcomes according to disease duration, in a study of more than 1,500 patients with onychomycosis. She found that the complete cure rate at 52 weeks dropped off markedly in patients with a history of onychomycosis for 1 year or longer at baseline.

Complete cure – defined as no clinical involvement of the target toenail along with both a negative potassium hydroxide examination and a negative fungal culture at 52 weeks – was achieved in 43% of efinaconazole-treated patients with onychomycosis for less than 1 year. The rate then plunged to 17% in those with a disease duration of 1-5 years and 16% in patients with onychomycosis for more than 5 years. Nevertheless, the topical antifungal was significantly more effective than was the vehicle, across the board, with complete cure rates in the vehicle group of roughly 18%, 5%, and 2%, respectively, in patients with onychomycosis for less than 1 year, 1-5 years, and more than 5 years (J Drugs Dermatol. 2015 Jan;14[1]:58-62).
 

Tackle coexisting tinea pedis

Podiatrists analyzed the combined efinaconazole outcome data based on whether participants had no coexisting tinea pedis, baseline tinea pedis treated concomitantly with an investigator-approved topical antifungal, or tinea pedis left untreated. They concluded that treatment of coexisting tinea pedis decisively enhanced the efficacy of efinaconazole for onychomycosis.

A total of 21% of study participants had concomitant tinea pedis, and 61% of them were treated for it. At week 52, the onychomycosis complete cure rate was 29% in the efinaconazole group concurrently treated for tinea pedis, compared with just 16% if their tinea pedis was untreated (J Am Podiatr Med Assoc. 2015 Sep;105[5]:407-11).

“If you see tinea pedis, don’t blow it off. Treat it. Otherwise, you’re not getting rid of the fungal reservoir,” Dr. Rosen emphasized.

He noted that two topical agents approved for tinea pedis – naftifine 2% cream or gel and luliconazole 1% cream – are effective as once-daily therapy for 2 weeks, a considerably briefer regimen than with other approved topicals. And short-course therapy spells improved adherence, he added.

In the pivotal trials, naftifine had an effective treatment rate – a clinically useful endpoint defined as a small amount of residual scaling and/or redness but no itching – of 57%, while for luliconazole the rates were 33%-48%.

These two agents also are approved for treatment of tinea corporis and tinea cruris. Naftifine is approved as a once-daily treatment for 2 weeks, while luliconazole is, notably, a 7-day treatment. Luliconazole, in particular, is a relatively expensive drug, Dr. Rosen added, so insurers may require prior failure on clotrimazole.
 

When to treat onychomycosis topically

The pivotal trials of tavaborole and efinaconazole were conducted in patients with 20%-60% nail involvement. The infection didn’t extend to the matrix, and nail thickness and crumbly subungual debris were modest at baseline.

“There are always potential safety issues – drug interactions, GI disturbance, taste loss, headache, teratogenicity, cardiotoxicity, hepatotoxicity – anytime you put a pill in your mouth. So if you have a patient who’s dedicated enough to use a topical for 48 weeks and it’s a modestly affected nail, think about it,” Dr. Rosen advised.

He reported serving on scientific advisory boards for Aclaris, Anacor, Cipla, and Valeant.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
 

[email protected]

KAUAI, HAWAII – Two keys to effective topical treatment of onychomycosis are treat it early and address coexisting tinea pedis, according to Theodore Rosen, MD.

A third element in achieving treatment success is to use one of the newer topical agents: efinaconazole (Jublia) or tavaborole (Kerydin). The efficacy of efinaconazole approaches that of terbinafine, the most effective and widely prescribed oral agent, which has a 59% rate of almost complete cure, defined as less than 10% residual abnormal nail with no requirement for mycologic cure.

Bruce Jancin/Frontline Medical News

And while tavaborole isn’t quite as effective, it’s definitely better than previous topical agents, Dr. Rosen said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

Both of these topicals are well tolerated and feature good nail permeation. They also allow for spread to the lateral nail folds and hyponychium. They even penetrate nail polish, although efinaconazole often causes the polish to lose its spiffy gloss, said Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston.

To underscore the importance of early treatment and addressing concomitant tinea pedis, he cited published secondary analyses of two identical double-blind, multicenter, 48-week clinical trials totaling 1,655 adults with onychomycosis who were randomized 3:1 to once-daily efinaconazole 10% topical solution or its vehicle.
 

Treat early

Phoebe Rich, MD, of the Oregon Dermatology and Research Center, Portland, broke down the outcomes according to disease duration, in a study of more than 1,500 patients with onychomycosis. She found that the complete cure rate at 52 weeks dropped off markedly in patients with a history of onychomycosis for 1 year or longer at baseline.

Complete cure – defined as no clinical involvement of the target toenail along with both a negative potassium hydroxide examination and a negative fungal culture at 52 weeks – was achieved in 43% of efinaconazole-treated patients with onychomycosis for less than 1 year. The rate then plunged to 17% in those with a disease duration of 1-5 years and 16% in patients with onychomycosis for more than 5 years. Nevertheless, the topical antifungal was significantly more effective than was the vehicle, across the board, with complete cure rates in the vehicle group of roughly 18%, 5%, and 2%, respectively, in patients with onychomycosis for less than 1 year, 1-5 years, and more than 5 years (J Drugs Dermatol. 2015 Jan;14[1]:58-62).
 

Tackle coexisting tinea pedis

Podiatrists analyzed the combined efinaconazole outcome data based on whether participants had no coexisting tinea pedis, baseline tinea pedis treated concomitantly with an investigator-approved topical antifungal, or tinea pedis left untreated. They concluded that treatment of coexisting tinea pedis decisively enhanced the efficacy of efinaconazole for onychomycosis.

A total of 21% of study participants had concomitant tinea pedis, and 61% of them were treated for it. At week 52, the onychomycosis complete cure rate was 29% in the efinaconazole group concurrently treated for tinea pedis, compared with just 16% if their tinea pedis was untreated (J Am Podiatr Med Assoc. 2015 Sep;105[5]:407-11).

“If you see tinea pedis, don’t blow it off. Treat it. Otherwise, you’re not getting rid of the fungal reservoir,” Dr. Rosen emphasized.

He noted that two topical agents approved for tinea pedis – naftifine 2% cream or gel and luliconazole 1% cream – are effective as once-daily therapy for 2 weeks, a considerably briefer regimen than with other approved topicals. And short-course therapy spells improved adherence, he added.

In the pivotal trials, naftifine had an effective treatment rate – a clinically useful endpoint defined as a small amount of residual scaling and/or redness but no itching – of 57%, while for luliconazole the rates were 33%-48%.

These two agents also are approved for treatment of tinea corporis and tinea cruris. Naftifine is approved as a once-daily treatment for 2 weeks, while luliconazole is, notably, a 7-day treatment. Luliconazole, in particular, is a relatively expensive drug, Dr. Rosen added, so insurers may require prior failure on clotrimazole.
 

When to treat onychomycosis topically

The pivotal trials of tavaborole and efinaconazole were conducted in patients with 20%-60% nail involvement. The infection didn’t extend to the matrix, and nail thickness and crumbly subungual debris were modest at baseline.

“There are always potential safety issues – drug interactions, GI disturbance, taste loss, headache, teratogenicity, cardiotoxicity, hepatotoxicity – anytime you put a pill in your mouth. So if you have a patient who’s dedicated enough to use a topical for 48 weeks and it’s a modestly affected nail, think about it,” Dr. Rosen advised.

He reported serving on scientific advisory boards for Aclaris, Anacor, Cipla, and Valeant.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
 

[email protected]

An international prognostic index for patients with chronic lymphocytic leukemia (CLL), known as CLL-IPI, was predictive of time from diagnosis to first treatment (TTFT) and 5-year median overall survival in patients across different risk categories treated with chemoimmunotherapy, according to a systematic review and meta-analysis published in Blood (2018 Jan 18;131[3]:365-8).

But limited data were available for patients treated with targeted therapies that are likely to have a profound effect on overall survival; thereby restricting the use of CLL-IPI in current clinical practice.

Novel therapies such as ibrutinib, idelalisib, and venetoclax have changed the treatment landscape for CLL, Stefano Molica, MD, of Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro, Italy, and his colleagues wrote. “Because observation remains the standard of care for asymptomatic early-stage patients, the introduction of these agents does not impact the utility of the CLL-IPI for predicting time from diagnosis to first treatment, but it likely has a profound impact on the survival of patients of all risk categories once treatment is indicated.”

The CLL-IPI tool, first published in 2016 to predict clinical outcomes in CLL patients, combines five parameters: age, clinical stage, TP53 status [normal vs. del(17p) and/or TP53 mutation], immunoglobulin heavy chain–variable mutational status, and serum b2-microglobulin. The prognostic tool was validated across several studies conducted in different countries with diverse practice settings, including academic hospitals, national population-based cohorts, and clinical trials.

The researchers conducted a systematic review and meta-analysis to understand the utility of CLL-IPI tool in predicting OS and TTFT across each risk category of CLL patients.

They included nine studies with 7,843 patients to assess the impact of the CLL-IPI on overall survival. The patient distribution into the CLL-IPI risk categories was low risk (median 45.9%), intermediate risk (median 30%), high risk (median 16.5%), and very high risk (median 3.6%).

The researchers relied on 11 series comprising 7,383 patients to assess 5-year survival probability, which was 92% for low risk, 81% for intermediate risk, 60% for high risk, and 34% for very high risk. They used seven studies comprising 5,206 patients to assess TTFT and found that the probability of remaining treatment free at 5 years was 82% in the low-risk group, 45% in the intermediate-risk group, 30% in the high-risk group, and 16% in the very-high-risk group.

Although a significant step toward harmonizing international prognostication for CLL, additional studies validating the utility of the CLL-IPI for predicting OS in patients treated with targeted therapy are needed, they wrote.

The researchers reported having no financial disclosures.

[email protected]

An international prognostic index for patients with chronic lymphocytic leukemia (CLL), known as CLL-IPI, was predictive of time from diagnosis to first treatment (TTFT) and 5-year median overall survival in patients across different risk categories treated with chemoimmunotherapy, according to a systematic review and meta-analysis published in Blood (2018 Jan 18;131[3]:365-8).

But limited data were available for patients treated with targeted therapies that are likely to have a profound effect on overall survival; thereby restricting the use of CLL-IPI in current clinical practice.

Novel therapies such as ibrutinib, idelalisib, and venetoclax have changed the treatment landscape for CLL, Stefano Molica, MD, of Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro, Italy, and his colleagues wrote. “Because observation remains the standard of care for asymptomatic early-stage patients, the introduction of these agents does not impact the utility of the CLL-IPI for predicting time from diagnosis to first treatment, but it likely has a profound impact on the survival of patients of all risk categories once treatment is indicated.”

The CLL-IPI tool, first published in 2016 to predict clinical outcomes in CLL patients, combines five parameters: age, clinical stage, TP53 status [normal vs. del(17p) and/or TP53 mutation], immunoglobulin heavy chain–variable mutational status, and serum b2-microglobulin. The prognostic tool was validated across several studies conducted in different countries with diverse practice settings, including academic hospitals, national population-based cohorts, and clinical trials.

The researchers conducted a systematic review and meta-analysis to understand the utility of CLL-IPI tool in predicting OS and TTFT across each risk category of CLL patients.

They included nine studies with 7,843 patients to assess the impact of the CLL-IPI on overall survival. The patient distribution into the CLL-IPI risk categories was low risk (median 45.9%), intermediate risk (median 30%), high risk (median 16.5%), and very high risk (median 3.6%).

The researchers relied on 11 series comprising 7,383 patients to assess 5-year survival probability, which was 92% for low risk, 81% for intermediate risk, 60% for high risk, and 34% for very high risk. They used seven studies comprising 5,206 patients to assess TTFT and found that the probability of remaining treatment free at 5 years was 82% in the low-risk group, 45% in the intermediate-risk group, 30% in the high-risk group, and 16% in the very-high-risk group.

Although a significant step toward harmonizing international prognostication for CLL, additional studies validating the utility of the CLL-IPI for predicting OS in patients treated with targeted therapy are needed, they wrote.

The researchers reported having no financial disclosures.

[email protected]

An international prognostic index for patients with chronic lymphocytic leukemia (CLL), known as CLL-IPI, was predictive of time from diagnosis to first treatment (TTFT) and 5-year median overall survival in patients across different risk categories treated with chemoimmunotherapy, according to a systematic review and meta-analysis published in Blood (2018 Jan 18;131[3]:365-8).

But limited data were available for patients treated with targeted therapies that are likely to have a profound effect on overall survival; thereby restricting the use of CLL-IPI in current clinical practice.

Novel therapies such as ibrutinib, idelalisib, and venetoclax have changed the treatment landscape for CLL, Stefano Molica, MD, of Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro, Italy, and his colleagues wrote. “Because observation remains the standard of care for asymptomatic early-stage patients, the introduction of these agents does not impact the utility of the CLL-IPI for predicting time from diagnosis to first treatment, but it likely has a profound impact on the survival of patients of all risk categories once treatment is indicated.”

The CLL-IPI tool, first published in 2016 to predict clinical outcomes in CLL patients, combines five parameters: age, clinical stage, TP53 status [normal vs. del(17p) and/or TP53 mutation], immunoglobulin heavy chain–variable mutational status, and serum b2-microglobulin. The prognostic tool was validated across several studies conducted in different countries with diverse practice settings, including academic hospitals, national population-based cohorts, and clinical trials.

The researchers conducted a systematic review and meta-analysis to understand the utility of CLL-IPI tool in predicting OS and TTFT across each risk category of CLL patients.

They included nine studies with 7,843 patients to assess the impact of the CLL-IPI on overall survival. The patient distribution into the CLL-IPI risk categories was low risk (median 45.9%), intermediate risk (median 30%), high risk (median 16.5%), and very high risk (median 3.6%).

The researchers relied on 11 series comprising 7,383 patients to assess 5-year survival probability, which was 92% for low risk, 81% for intermediate risk, 60% for high risk, and 34% for very high risk. They used seven studies comprising 5,206 patients to assess TTFT and found that the probability of remaining treatment free at 5 years was 82% in the low-risk group, 45% in the intermediate-risk group, 30% in the high-risk group, and 16% in the very-high-risk group.

Although a significant step toward harmonizing international prognostication for CLL, additional studies validating the utility of the CLL-IPI for predicting OS in patients treated with targeted therapy are needed, they wrote.

The researchers reported having no financial disclosures.

[email protected]