Leukemia, Myelodysplasia, Transplantation

EDINBURGH – Routine empiric prophylaxis against pneumocystis jiroveci pneumonia (PJP) may be unwarranted in chronic lymphocytic leukemia patients initiating Bruton tyrosine kinase (BTK) inhibitor therapy, a retrospective chart review suggests.

Among 212 patients with chronic lymphocytic leukemia (CLL) who were treated with ibrutinib or acalabrutinib either as monotherapy or as part of a combination regimen for at least 30 days between Jan. 1, 2010, and Feb. 1, 2019, at Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, 125 (59%) received PJP prophylaxis, including either trimethoprim-sulfamethoxazole (74%) or atovaquone (26%), Christine Ryan, MD, reported at the International Workshop on CLL.

Two PJP cases occurred in the 120 patients on single-agent ibrutinib, including one in a previously untreated patient and one in a patient with relapsed/refractory CLL. Neither patient had received PJP prophylaxis, said Dr. Ryan, a senior resident at Brigham and Women’s Hospital.

No PJP cases occurred in the 21 patients who received acalabrutinib monotherapy or in the 14 patients who received acalabrutinib combination therapy, and 1 occurred in a trial cohort of 57 patients receiving frontline ibrutinib plus fludarabine-based chemotherapy (FCR). The latter had been prescribed PJP prophylaxis, but “unfortunately self-discontinued the prophylaxis” 2 months prior to the infection, Dr. Ryan said.

“The overall prevalence of PJP in patients not on prophylaxis was 3.4%, there were no cases of PJP in patients on prophylaxis, and the incidence rate in patients not on prophylaxis was 1.9 per 100 person-years, with a number needed to treat to prevent 1 case of PJP calculated to be 42 patients,” she said.

In addition to PJP, three cases of proven or probable invasive fungal infections (IFI) occurred, including one case of pulmonary histoplasmosis in the ibrutinib plus FCR trial cohort and two cases of aspergillosis, including a pulmonary case and a brain abscess, in an ibrutinib plus umbralisib trial cohort.

“The overall prevalence of aspergillosis or histoplasmosis in our entire cohort was 1.4%, and notably there were no cases of IFI in the single-agent therapy cohort, but the prevalence in the ibrutinib-combination therapy patients was 4.2%,” Dr. Ryan said.

Patients included in the review were adults with a median age of 64.8 years, and 64% were men. The median duration of BTK inhibitor therapy was 23.2 months.

“We know that CLL patients treated with fludarabine have an increased risk of PJP,” she said. “As such, it is routinely recommended that patients receiving fludarabine-containing chemotherapy regimens are prescribed PJP prophylaxis.”

Additionally, the increasing use of oral BTK inhibitors has raised concerns about the potential risk of PJP or other IFIs in patients on those agents, Dr. Ryan explained, noting that existing case reports and case series looking at PJP have shown varying prevalence rates, and little is known about the effects of prophylaxis.

“At present, there are no international guidelines regarding the use of antimicrobial prophylaxis in CLL patients treated with BTK inhibitors, and prophylaxis practices vary widely across countries and institutions,” she said.

The findings of the current study demonstrate that such variation exists “even within our own institution,” Dr. Ryan added.

The findings also show an overall low PJP prevalence of 3.4% in patients not receiving prophylaxis, which falls below the “commonly accepted threshold of 5%, above which routine prophylaxis becomes recommended,” she said.

“Overall, our data suggest that routine PJP or IFI prophylaxis in patients receiving BTK inhibitors may not be needed, but this is definitely an area that requires further study, ideally with a prospective trial with a larger sample size and multiple institutions, to support the development of consensus guidelines on this issue,” she said.

Dr. Ryan reported having no financial disclosures.

[email protected]

EDINBURGH – Routine empiric prophylaxis against pneumocystis jiroveci pneumonia (PJP) may be unwarranted in chronic lymphocytic leukemia patients initiating Bruton tyrosine kinase (BTK) inhibitor therapy, a retrospective chart review suggests.

Among 212 patients with chronic lymphocytic leukemia (CLL) who were treated with ibrutinib or acalabrutinib either as monotherapy or as part of a combination regimen for at least 30 days between Jan. 1, 2010, and Feb. 1, 2019, at Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, 125 (59%) received PJP prophylaxis, including either trimethoprim-sulfamethoxazole (74%) or atovaquone (26%), Christine Ryan, MD, reported at the International Workshop on CLL.

Two PJP cases occurred in the 120 patients on single-agent ibrutinib, including one in a previously untreated patient and one in a patient with relapsed/refractory CLL. Neither patient had received PJP prophylaxis, said Dr. Ryan, a senior resident at Brigham and Women’s Hospital.

No PJP cases occurred in the 21 patients who received acalabrutinib monotherapy or in the 14 patients who received acalabrutinib combination therapy, and 1 occurred in a trial cohort of 57 patients receiving frontline ibrutinib plus fludarabine-based chemotherapy (FCR). The latter had been prescribed PJP prophylaxis, but “unfortunately self-discontinued the prophylaxis” 2 months prior to the infection, Dr. Ryan said.

“The overall prevalence of PJP in patients not on prophylaxis was 3.4%, there were no cases of PJP in patients on prophylaxis, and the incidence rate in patients not on prophylaxis was 1.9 per 100 person-years, with a number needed to treat to prevent 1 case of PJP calculated to be 42 patients,” she said.

In addition to PJP, three cases of proven or probable invasive fungal infections (IFI) occurred, including one case of pulmonary histoplasmosis in the ibrutinib plus FCR trial cohort and two cases of aspergillosis, including a pulmonary case and a brain abscess, in an ibrutinib plus umbralisib trial cohort.

“The overall prevalence of aspergillosis or histoplasmosis in our entire cohort was 1.4%, and notably there were no cases of IFI in the single-agent therapy cohort, but the prevalence in the ibrutinib-combination therapy patients was 4.2%,” Dr. Ryan said.

Patients included in the review were adults with a median age of 64.8 years, and 64% were men. The median duration of BTK inhibitor therapy was 23.2 months.

“We know that CLL patients treated with fludarabine have an increased risk of PJP,” she said. “As such, it is routinely recommended that patients receiving fludarabine-containing chemotherapy regimens are prescribed PJP prophylaxis.”

Additionally, the increasing use of oral BTK inhibitors has raised concerns about the potential risk of PJP or other IFIs in patients on those agents, Dr. Ryan explained, noting that existing case reports and case series looking at PJP have shown varying prevalence rates, and little is known about the effects of prophylaxis.

“At present, there are no international guidelines regarding the use of antimicrobial prophylaxis in CLL patients treated with BTK inhibitors, and prophylaxis practices vary widely across countries and institutions,” she said.

The findings of the current study demonstrate that such variation exists “even within our own institution,” Dr. Ryan added.

The findings also show an overall low PJP prevalence of 3.4% in patients not receiving prophylaxis, which falls below the “commonly accepted threshold of 5%, above which routine prophylaxis becomes recommended,” she said.

“Overall, our data suggest that routine PJP or IFI prophylaxis in patients receiving BTK inhibitors may not be needed, but this is definitely an area that requires further study, ideally with a prospective trial with a larger sample size and multiple institutions, to support the development of consensus guidelines on this issue,” she said.

Dr. Ryan reported having no financial disclosures.

[email protected]

EDINBURGH – Routine empiric prophylaxis against pneumocystis jiroveci pneumonia (PJP) may be unwarranted in chronic lymphocytic leukemia patients initiating Bruton tyrosine kinase (BTK) inhibitor therapy, a retrospective chart review suggests.

Among 212 patients with chronic lymphocytic leukemia (CLL) who were treated with ibrutinib or acalabrutinib either as monotherapy or as part of a combination regimen for at least 30 days between Jan. 1, 2010, and Feb. 1, 2019, at Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, 125 (59%) received PJP prophylaxis, including either trimethoprim-sulfamethoxazole (74%) or atovaquone (26%), Christine Ryan, MD, reported at the International Workshop on CLL.

Two PJP cases occurred in the 120 patients on single-agent ibrutinib, including one in a previously untreated patient and one in a patient with relapsed/refractory CLL. Neither patient had received PJP prophylaxis, said Dr. Ryan, a senior resident at Brigham and Women’s Hospital.

No PJP cases occurred in the 21 patients who received acalabrutinib monotherapy or in the 14 patients who received acalabrutinib combination therapy, and 1 occurred in a trial cohort of 57 patients receiving frontline ibrutinib plus fludarabine-based chemotherapy (FCR). The latter had been prescribed PJP prophylaxis, but “unfortunately self-discontinued the prophylaxis” 2 months prior to the infection, Dr. Ryan said.

“The overall prevalence of PJP in patients not on prophylaxis was 3.4%, there were no cases of PJP in patients on prophylaxis, and the incidence rate in patients not on prophylaxis was 1.9 per 100 person-years, with a number needed to treat to prevent 1 case of PJP calculated to be 42 patients,” she said.

In addition to PJP, three cases of proven or probable invasive fungal infections (IFI) occurred, including one case of pulmonary histoplasmosis in the ibrutinib plus FCR trial cohort and two cases of aspergillosis, including a pulmonary case and a brain abscess, in an ibrutinib plus umbralisib trial cohort.

“The overall prevalence of aspergillosis or histoplasmosis in our entire cohort was 1.4%, and notably there were no cases of IFI in the single-agent therapy cohort, but the prevalence in the ibrutinib-combination therapy patients was 4.2%,” Dr. Ryan said.

Patients included in the review were adults with a median age of 64.8 years, and 64% were men. The median duration of BTK inhibitor therapy was 23.2 months.

“We know that CLL patients treated with fludarabine have an increased risk of PJP,” she said. “As such, it is routinely recommended that patients receiving fludarabine-containing chemotherapy regimens are prescribed PJP prophylaxis.”

Additionally, the increasing use of oral BTK inhibitors has raised concerns about the potential risk of PJP or other IFIs in patients on those agents, Dr. Ryan explained, noting that existing case reports and case series looking at PJP have shown varying prevalence rates, and little is known about the effects of prophylaxis.

“At present, there are no international guidelines regarding the use of antimicrobial prophylaxis in CLL patients treated with BTK inhibitors, and prophylaxis practices vary widely across countries and institutions,” she said.

The findings of the current study demonstrate that such variation exists “even within our own institution,” Dr. Ryan added.

The findings also show an overall low PJP prevalence of 3.4% in patients not receiving prophylaxis, which falls below the “commonly accepted threshold of 5%, above which routine prophylaxis becomes recommended,” she said.

“Overall, our data suggest that routine PJP or IFI prophylaxis in patients receiving BTK inhibitors may not be needed, but this is definitely an area that requires further study, ideally with a prospective trial with a larger sample size and multiple institutions, to support the development of consensus guidelines on this issue,” she said.

Dr. Ryan reported having no financial disclosures.

[email protected]

A pooled analysis suggests adverse cytogenetics are a key factor negatively impacting outcomes in patients with NPM1^mut/FLT3-ITD^neg/low acute myeloid leukemia (AML).

National Institutes of Health/Wikimedia Commons/Public Domain

In patients with adverse chromosomal abnormalities, NPM1 mutational status was found not to confer a favorable outcome. The findings suggest cytogenetic risk outweighs molecular risk in patients with NPM1 mutations and the FLT3-ITD^neg/low genotype.

“Patients carrying adverse-risk cytogenetics shared a virtually identical unfavorable outcome, regardless of whether the otherwise beneficial NPM1^mut/FLT3-ITD^neg/low status was present. The type of the adverse chromosomal abnormality did not seem to influence this effect, although low numbers might obscure detection of heterogeneity among individual aberrations,” Linus Angenendt, MD, of University Hospital Munster (Germany) and colleagues, wrote in the Journal of Clinical Oncology.

The researchers retrospectively analyzed 2,426 patients with NPM1^mut/FLT3-ITD^neg/low AML. Of these, 17.6% had an abnormal karyotype, and 3.4% had adverse-risk chromosomal aberrations.

Prior to analysis, individual patient data were pooled from nine international AML study group registries or treatment centers.

After analysis, the researchers found that adverse cytogenetics were associated with inferior complete remission rates (66.3%), compared with in patients with normal karyotype or intermediate-risk cytogenetic abnormalities (87.7% and 86.0%, respectively; P less than .001). The complete remission rates for the NPM1^mut/FLT3-ITD^neg/low AML adverse cytogenetics group was similar to patients with NPM1^wt/FLT3-ITD^neg/low and adverse cytogenetic abnormalities (66.3% vs. 57.5%).

Five-year event-free survival rates and overall survival rates were also lower in patients with NPM1^mut/FLT3-ITD^neg/low AML and adverse cytogenetics, compared with patients with normal karyotype or intermediate-risk cytogenetic abnormalities (P less than .001).

“Even though the combination of an NPM1 mutation with these abnormalities is rare, the prognostic effect of adverse cytogenetics in NPM1^mut AML has important implications for postremission treatment decisions, in particular, the current recommendation that patients who are NPM1^mut/FLT3-ITD^neg/low not receive allogeneic hematopoietic stem cell transplantation (HSCT), given their presumed low risk of relapse might be altered if the adverse karyotype increased the risk,” they wrote.

The type of chromosomal aberration did not appear to impact this effect, but the small sample size may have hindered the ability to detect a difference between different abnormalities, the researchers noted.

One key limitation of the study was the retrospective design. As a result, in patients with an abnormal karyotype, some genetic analyses could have been underutilized.

“These results demand additional validation within prospective trials,” the researchers concluded.

The study was funded by the University of Munster Medical School, the German Research Foundation, the French government, the Ministry of Health of the Czech Republic, and others. The authors reported financial affiliations with numerous pharmaceutical companies.

SOURCE: Angenendt L et al. J Clin Oncol. 2019 Oct 10;37(29):2632-42.

A pooled analysis suggests adverse cytogenetics are a key factor negatively impacting outcomes in patients with NPM1^mut/FLT3-ITD^neg/low acute myeloid leukemia (AML).

National Institutes of Health/Wikimedia Commons/Public Domain

In patients with adverse chromosomal abnormalities, NPM1 mutational status was found not to confer a favorable outcome. The findings suggest cytogenetic risk outweighs molecular risk in patients with NPM1 mutations and the FLT3-ITD^neg/low genotype.

“Patients carrying adverse-risk cytogenetics shared a virtually identical unfavorable outcome, regardless of whether the otherwise beneficial NPM1^mut/FLT3-ITD^neg/low status was present. The type of the adverse chromosomal abnormality did not seem to influence this effect, although low numbers might obscure detection of heterogeneity among individual aberrations,” Linus Angenendt, MD, of University Hospital Munster (Germany) and colleagues, wrote in the Journal of Clinical Oncology.

The researchers retrospectively analyzed 2,426 patients with NPM1^mut/FLT3-ITD^neg/low AML. Of these, 17.6% had an abnormal karyotype, and 3.4% had adverse-risk chromosomal aberrations.

Prior to analysis, individual patient data were pooled from nine international AML study group registries or treatment centers.

After analysis, the researchers found that adverse cytogenetics were associated with inferior complete remission rates (66.3%), compared with in patients with normal karyotype or intermediate-risk cytogenetic abnormalities (87.7% and 86.0%, respectively; P less than .001). The complete remission rates for the NPM1^mut/FLT3-ITD^neg/low AML adverse cytogenetics group was similar to patients with NPM1^wt/FLT3-ITD^neg/low and adverse cytogenetic abnormalities (66.3% vs. 57.5%).

Five-year event-free survival rates and overall survival rates were also lower in patients with NPM1^mut/FLT3-ITD^neg/low AML and adverse cytogenetics, compared with patients with normal karyotype or intermediate-risk cytogenetic abnormalities (P less than .001).

“Even though the combination of an NPM1 mutation with these abnormalities is rare, the prognostic effect of adverse cytogenetics in NPM1^mut AML has important implications for postremission treatment decisions, in particular, the current recommendation that patients who are NPM1^mut/FLT3-ITD^neg/low not receive allogeneic hematopoietic stem cell transplantation (HSCT), given their presumed low risk of relapse might be altered if the adverse karyotype increased the risk,” they wrote.

The type of chromosomal aberration did not appear to impact this effect, but the small sample size may have hindered the ability to detect a difference between different abnormalities, the researchers noted.

One key limitation of the study was the retrospective design. As a result, in patients with an abnormal karyotype, some genetic analyses could have been underutilized.

“These results demand additional validation within prospective trials,” the researchers concluded.

The study was funded by the University of Munster Medical School, the German Research Foundation, the French government, the Ministry of Health of the Czech Republic, and others. The authors reported financial affiliations with numerous pharmaceutical companies.

SOURCE: Angenendt L et al. J Clin Oncol. 2019 Oct 10;37(29):2632-42.

A pooled analysis suggests adverse cytogenetics are a key factor negatively impacting outcomes in patients with NPM1^mut/FLT3-ITD^neg/low acute myeloid leukemia (AML).

National Institutes of Health/Wikimedia Commons/Public Domain

In patients with adverse chromosomal abnormalities, NPM1 mutational status was found not to confer a favorable outcome. The findings suggest cytogenetic risk outweighs molecular risk in patients with NPM1 mutations and the FLT3-ITD^neg/low genotype.

“Patients carrying adverse-risk cytogenetics shared a virtually identical unfavorable outcome, regardless of whether the otherwise beneficial NPM1^mut/FLT3-ITD^neg/low status was present. The type of the adverse chromosomal abnormality did not seem to influence this effect, although low numbers might obscure detection of heterogeneity among individual aberrations,” Linus Angenendt, MD, of University Hospital Munster (Germany) and colleagues, wrote in the Journal of Clinical Oncology.

The researchers retrospectively analyzed 2,426 patients with NPM1^mut/FLT3-ITD^neg/low AML. Of these, 17.6% had an abnormal karyotype, and 3.4% had adverse-risk chromosomal aberrations.

Prior to analysis, individual patient data were pooled from nine international AML study group registries or treatment centers.

After analysis, the researchers found that adverse cytogenetics were associated with inferior complete remission rates (66.3%), compared with in patients with normal karyotype or intermediate-risk cytogenetic abnormalities (87.7% and 86.0%, respectively; P less than .001). The complete remission rates for the NPM1^mut/FLT3-ITD^neg/low AML adverse cytogenetics group was similar to patients with NPM1^wt/FLT3-ITD^neg/low and adverse cytogenetic abnormalities (66.3% vs. 57.5%).

Five-year event-free survival rates and overall survival rates were also lower in patients with NPM1^mut/FLT3-ITD^neg/low AML and adverse cytogenetics, compared with patients with normal karyotype or intermediate-risk cytogenetic abnormalities (P less than .001).

“Even though the combination of an NPM1 mutation with these abnormalities is rare, the prognostic effect of adverse cytogenetics in NPM1^mut AML has important implications for postremission treatment decisions, in particular, the current recommendation that patients who are NPM1^mut/FLT3-ITD^neg/low not receive allogeneic hematopoietic stem cell transplantation (HSCT), given their presumed low risk of relapse might be altered if the adverse karyotype increased the risk,” they wrote.

The type of chromosomal aberration did not appear to impact this effect, but the small sample size may have hindered the ability to detect a difference between different abnormalities, the researchers noted.

One key limitation of the study was the retrospective design. As a result, in patients with an abnormal karyotype, some genetic analyses could have been underutilized.

“These results demand additional validation within prospective trials,” the researchers concluded.

The study was funded by the University of Munster Medical School, the German Research Foundation, the French government, the Ministry of Health of the Czech Republic, and others. The authors reported financial affiliations with numerous pharmaceutical companies.

SOURCE: Angenendt L et al. J Clin Oncol. 2019 Oct 10;37(29):2632-42.

SAN FRANCISCO – Should targeted agents replace chemoimmunotherapy (CIT) as first-line treatment for chronic lymphocytic leukemia (CLL)? A recent debate suggests there’s no consensus.

Jennifer Smith/MDedge News

William G. Wierda, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute in Boston, debated the topic at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

Dr. Wierda argued that CLL patients should receive a BTK inhibitor or BCL2 inhibitor, with or without obinutuzumab, as first-line therapy because these targeted agents have been shown to provide better progression-free survival (PFS) than CIT, and the targeted therapies may prolong overall survival (OS) as well.

Dr. Brown countered that targeted agents don’t improve PFS for all CLL patients, improved PFS doesn’t always translate to improved OS, and targeted agents cost more than CIT.
 

No role for CIT as first-line treatment

“We have two approaches right now, with nonchemoimmunotherapy-based treatment,” Dr. Wierda said. “One approach, with small-molecule inhibitors, is to have a sustained and durable period of disease control, particularly with BTK inhibitors. The other strategy that has emerged is deep remissions with fixed-duration treatment with BCL2 small-molecule inhibitor-based therapy, which, I would argue, is better than being exposed to genotoxic chemoimmunotherapy.”

Dr. Wierda went on to explain that the BTK inhibitor ibrutinib has been shown to improve PFS, compared with CIT, in phase 3 trials.

In the iLLUMINATE trial, researchers compared ibrutinib plus obinutuzumab to chlorambucil plus obinutuzumab as first-line treatment in CLL. At a median follow-up of 31.3 months, the median PFS was not reached in the ibrutinib arm and was 19 months in the chlorambucil arm (P less than .0001; Lancet Oncol. 2019 Jan;20[1]:43-56).

In the A041202 study, researchers compared ibrutinib alone (Ib) or in combination with rituximab (Ib-R) to bendamustine plus rituximab (BR) in untreated, older patients with CLL. The 2-year PFS estimates were 74% in the BR arm, 87% in the Ib arm, and 88% in the Ib-R arm (P less than .001 for BR vs. Ib or Ib-R; N Engl J Med. 2018; 379:2517-28).

In the E1912 trial, researchers compared Ib-R to fludarabine, cyclophosphamide, and rituximab (FCR) in younger, untreated CLL patients. The 3-year PFS was 89.4% with Ib-R and 72.9% with FCR (P less than .001; N Engl J Med. 2019 Aug 1;381:432-43).

Dr. Wierda noted that the E1912 trial also showed superior OS with Ib-R. The 3-year OS rate was 98.8% with Ib-R and 91.5% with FCR (P less than .001). However, there was no significant difference in OS between the treatment arms in the A041202 trial or the iLLUMINATE trial.

“But I would argue that is, in part, because of short follow-up,” Dr. Wierda said. “The trials were all designed to look at progression-free survival, not overall survival. With longer follow-up, we may see differences in overall survival emerging.”

Dr. Wierda went on to say that fixed‐duration treatment with the BCL2 inhibitor venetoclax can improve PFS over CIT.

In the phase 3 CLL14 trial, researchers compared fixed-duration treatment with venetoclax plus obinutuzumab to chlorambucil plus obinutuzumab in previously untreated CLL patients with comorbidities. The estimated PFS at 2 years was 88.2% in the venetoclax group and 64.1% in the chlorambucil group (P less than .001; N Engl J Med. 2019; 380:2225-36).

“[There was] no difference in overall survival,” Dr. Wierda noted. “But, again, I would argue ... that follow-up is relatively limited. We may ultimately see a difference in overall survival.”

Based on these findings, Dr. Wierda made the following treatment recommendations:

• Any CLL patient with del(17p) or TP53 mutation, and older, unfit patients with unmutated IGHV should receive a BTK inhibitor, with or without obinutuzumab.
• All young, fit patients, and older, unfit patients with mutated IGHV should receive a BCL2 inhibitor plus obinutuzumab.

Dr. Wierda also noted that ibrutinib and venetoclax in combination have shown early promise for patients with previously untreated CLL (N Engl J Med. 2019; 380:2095-2103).
 

CIT still has a role as first-line treatment

Dr. Brown suggested that a PFS benefit may not be enough to recommend targeted agents over CIT. For one thing, the PFS benefit doesn’t apply to all patients, as the IGHV-mutated subgroup does equally well with CIT and targeted agents.

Jennifer Smith/MDedge News

In the IGHV-mutated group from the E1912 trial, the 3-year PFS was 88% for patients who received Ib-R and those who received FCR (N Engl J Med. 2019 Aug 1;381:432-43). In the A041202 study, the 2-year PFS among IGHV-mutated patients was 87% in the BR arm, 86% in the Ib arm, and 88% in the Ib-R arm (N Engl J Med. 2018; 379:2517-28).

In the CLL14 trial, PFS rates were similar among IGHV-mutated patients who received chlorambucil plus obinutuzumab and IGHV-mutated or unmutated patients who received venetoclax and obinutuzumab (N Engl J Med. 2019; 380:2225-36).

Dr. Brown also noted that the overall improvement in PFS observed with ibrutinib and venetoclax doesn’t always translate to improved OS.

In the A041202 study, there was no significant difference in OS between the Ib, Ib-R, and BR arms (N Engl J Med. 2018; 379:2517-28). There was no significant difference in OS between the ibrutinib and chlorambucil arms in the iLLUMINATE trial (Lancet Oncol. 2019 Jan;20[1]:43-56). And there was no significant difference in OS between the venetoclax and chlorambucil arms in the CLL14 trial (N Engl J Med. 2019; 380:2225-36).

However, in the RESONATE-2 trial, ibrutinib provided an OS benefit over chlorambucil. The 2-year OS was 95% and 84%, respectively (P = .0145; Haematologica. Sept 2018;103:1502-10). Dr. Brown said the OS advantage in this study was due to the “very poor comparator of chlorambucil and very limited crossover.”

As Dr. Wierda mentioned, the OS rate was higher with Ib-R than with FCR in the E1912 trial. The 3-year OS rate was 98.8% and 91.5%, respectively (P less than .001; N Engl J Med. 2019 Aug 1;381:432-43). Dr. Brown noted, however, that there were few deaths in this study, and many of them “were not clearly related to the disease or its treatment.”

Dr. Brown also pointed out that FCR has been shown to have curative potential in IGHV-mutated CLL in both the FCR300 trial (Blood. 2016 127:303-9) and the CLL8 trial (Blood. 2016 127:208-15).

Another factor to consider is the greater cost of targeted agents. One analysis suggested the per-patient lifetime cost of CLL treatment in the United States will increase from $147,000 to $604,000 as targeted therapies overtake CIT as first-line treatment (J Clin Oncol. 2017 Jan 10;35[2]:166-174).

“Given all of the above, chemoimmunotherapy is going to remain part of the treatment repertoire for CLL,” Dr. Brown said. “It’s our only known potential cure for the fit, mutated patients ... and can also result in prolonged treatment-free intervals for patients who are older. As we manage CLL as a chronic disease over a lifetime, we need to continue to have this in our armamentarium.”

Specifically, Dr. Brown said CIT is appropriate for patients who don’t have del(17p) or mutated TP53. FCR should be given to young, fit patients with IGHV-mutated CLL, and FCR or BR should be given to older patients and young, fit patients with IGHV-unmutated CLL.

Dr. Brown and Dr. Wierda reported financial ties to multiple pharmaceutical companies, including makers of CLL treatments.

[email protected]

SAN FRANCISCO – Should targeted agents replace chemoimmunotherapy (CIT) as first-line treatment for chronic lymphocytic leukemia (CLL)? A recent debate suggests there’s no consensus.

Jennifer Smith/MDedge News

William G. Wierda, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute in Boston, debated the topic at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

Dr. Wierda argued that CLL patients should receive a BTK inhibitor or BCL2 inhibitor, with or without obinutuzumab, as first-line therapy because these targeted agents have been shown to provide better progression-free survival (PFS) than CIT, and the targeted therapies may prolong overall survival (OS) as well.

Dr. Brown countered that targeted agents don’t improve PFS for all CLL patients, improved PFS doesn’t always translate to improved OS, and targeted agents cost more than CIT.
 

No role for CIT as first-line treatment

“We have two approaches right now, with nonchemoimmunotherapy-based treatment,” Dr. Wierda said. “One approach, with small-molecule inhibitors, is to have a sustained and durable period of disease control, particularly with BTK inhibitors. The other strategy that has emerged is deep remissions with fixed-duration treatment with BCL2 small-molecule inhibitor-based therapy, which, I would argue, is better than being exposed to genotoxic chemoimmunotherapy.”

Dr. Wierda went on to explain that the BTK inhibitor ibrutinib has been shown to improve PFS, compared with CIT, in phase 3 trials.

In the iLLUMINATE trial, researchers compared ibrutinib plus obinutuzumab to chlorambucil plus obinutuzumab as first-line treatment in CLL. At a median follow-up of 31.3 months, the median PFS was not reached in the ibrutinib arm and was 19 months in the chlorambucil arm (P less than .0001; Lancet Oncol. 2019 Jan;20[1]:43-56).

In the A041202 study, researchers compared ibrutinib alone (Ib) or in combination with rituximab (Ib-R) to bendamustine plus rituximab (BR) in untreated, older patients with CLL. The 2-year PFS estimates were 74% in the BR arm, 87% in the Ib arm, and 88% in the Ib-R arm (P less than .001 for BR vs. Ib or Ib-R; N Engl J Med. 2018; 379:2517-28).

In the E1912 trial, researchers compared Ib-R to fludarabine, cyclophosphamide, and rituximab (FCR) in younger, untreated CLL patients. The 3-year PFS was 89.4% with Ib-R and 72.9% with FCR (P less than .001; N Engl J Med. 2019 Aug 1;381:432-43).

Dr. Wierda noted that the E1912 trial also showed superior OS with Ib-R. The 3-year OS rate was 98.8% with Ib-R and 91.5% with FCR (P less than .001). However, there was no significant difference in OS between the treatment arms in the A041202 trial or the iLLUMINATE trial.

“But I would argue that is, in part, because of short follow-up,” Dr. Wierda said. “The trials were all designed to look at progression-free survival, not overall survival. With longer follow-up, we may see differences in overall survival emerging.”

Dr. Wierda went on to say that fixed‐duration treatment with the BCL2 inhibitor venetoclax can improve PFS over CIT.

In the phase 3 CLL14 trial, researchers compared fixed-duration treatment with venetoclax plus obinutuzumab to chlorambucil plus obinutuzumab in previously untreated CLL patients with comorbidities. The estimated PFS at 2 years was 88.2% in the venetoclax group and 64.1% in the chlorambucil group (P less than .001; N Engl J Med. 2019; 380:2225-36).

“[There was] no difference in overall survival,” Dr. Wierda noted. “But, again, I would argue ... that follow-up is relatively limited. We may ultimately see a difference in overall survival.”

Based on these findings, Dr. Wierda made the following treatment recommendations:

• Any CLL patient with del(17p) or TP53 mutation, and older, unfit patients with unmutated IGHV should receive a BTK inhibitor, with or without obinutuzumab.
• All young, fit patients, and older, unfit patients with mutated IGHV should receive a BCL2 inhibitor plus obinutuzumab.

Dr. Wierda also noted that ibrutinib and venetoclax in combination have shown early promise for patients with previously untreated CLL (N Engl J Med. 2019; 380:2095-2103).
 

CIT still has a role as first-line treatment

Dr. Brown suggested that a PFS benefit may not be enough to recommend targeted agents over CIT. For one thing, the PFS benefit doesn’t apply to all patients, as the IGHV-mutated subgroup does equally well with CIT and targeted agents.

Jennifer Smith/MDedge News

In the IGHV-mutated group from the E1912 trial, the 3-year PFS was 88% for patients who received Ib-R and those who received FCR (N Engl J Med. 2019 Aug 1;381:432-43). In the A041202 study, the 2-year PFS among IGHV-mutated patients was 87% in the BR arm, 86% in the Ib arm, and 88% in the Ib-R arm (N Engl J Med. 2018; 379:2517-28).

In the CLL14 trial, PFS rates were similar among IGHV-mutated patients who received chlorambucil plus obinutuzumab and IGHV-mutated or unmutated patients who received venetoclax and obinutuzumab (N Engl J Med. 2019; 380:2225-36).

Dr. Brown also noted that the overall improvement in PFS observed with ibrutinib and venetoclax doesn’t always translate to improved OS.

In the A041202 study, there was no significant difference in OS between the Ib, Ib-R, and BR arms (N Engl J Med. 2018; 379:2517-28). There was no significant difference in OS between the ibrutinib and chlorambucil arms in the iLLUMINATE trial (Lancet Oncol. 2019 Jan;20[1]:43-56). And there was no significant difference in OS between the venetoclax and chlorambucil arms in the CLL14 trial (N Engl J Med. 2019; 380:2225-36).

However, in the RESONATE-2 trial, ibrutinib provided an OS benefit over chlorambucil. The 2-year OS was 95% and 84%, respectively (P = .0145; Haematologica. Sept 2018;103:1502-10). Dr. Brown said the OS advantage in this study was due to the “very poor comparator of chlorambucil and very limited crossover.”

As Dr. Wierda mentioned, the OS rate was higher with Ib-R than with FCR in the E1912 trial. The 3-year OS rate was 98.8% and 91.5%, respectively (P less than .001; N Engl J Med. 2019 Aug 1;381:432-43). Dr. Brown noted, however, that there were few deaths in this study, and many of them “were not clearly related to the disease or its treatment.”

Dr. Brown also pointed out that FCR has been shown to have curative potential in IGHV-mutated CLL in both the FCR300 trial (Blood. 2016 127:303-9) and the CLL8 trial (Blood. 2016 127:208-15).

Another factor to consider is the greater cost of targeted agents. One analysis suggested the per-patient lifetime cost of CLL treatment in the United States will increase from $147,000 to $604,000 as targeted therapies overtake CIT as first-line treatment (J Clin Oncol. 2017 Jan 10;35[2]:166-174).

“Given all of the above, chemoimmunotherapy is going to remain part of the treatment repertoire for CLL,” Dr. Brown said. “It’s our only known potential cure for the fit, mutated patients ... and can also result in prolonged treatment-free intervals for patients who are older. As we manage CLL as a chronic disease over a lifetime, we need to continue to have this in our armamentarium.”

Specifically, Dr. Brown said CIT is appropriate for patients who don’t have del(17p) or mutated TP53. FCR should be given to young, fit patients with IGHV-mutated CLL, and FCR or BR should be given to older patients and young, fit patients with IGHV-unmutated CLL.

Dr. Brown and Dr. Wierda reported financial ties to multiple pharmaceutical companies, including makers of CLL treatments.

[email protected]

SAN FRANCISCO – Should targeted agents replace chemoimmunotherapy (CIT) as first-line treatment for chronic lymphocytic leukemia (CLL)? A recent debate suggests there’s no consensus.

Jennifer Smith/MDedge News

William G. Wierda, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute in Boston, debated the topic at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

Dr. Wierda argued that CLL patients should receive a BTK inhibitor or BCL2 inhibitor, with or without obinutuzumab, as first-line therapy because these targeted agents have been shown to provide better progression-free survival (PFS) than CIT, and the targeted therapies may prolong overall survival (OS) as well.

Dr. Brown countered that targeted agents don’t improve PFS for all CLL patients, improved PFS doesn’t always translate to improved OS, and targeted agents cost more than CIT.
 

No role for CIT as first-line treatment

“We have two approaches right now, with nonchemoimmunotherapy-based treatment,” Dr. Wierda said. “One approach, with small-molecule inhibitors, is to have a sustained and durable period of disease control, particularly with BTK inhibitors. The other strategy that has emerged is deep remissions with fixed-duration treatment with BCL2 small-molecule inhibitor-based therapy, which, I would argue, is better than being exposed to genotoxic chemoimmunotherapy.”

Dr. Wierda went on to explain that the BTK inhibitor ibrutinib has been shown to improve PFS, compared with CIT, in phase 3 trials.

In the iLLUMINATE trial, researchers compared ibrutinib plus obinutuzumab to chlorambucil plus obinutuzumab as first-line treatment in CLL. At a median follow-up of 31.3 months, the median PFS was not reached in the ibrutinib arm and was 19 months in the chlorambucil arm (P less than .0001; Lancet Oncol. 2019 Jan;20[1]:43-56).

In the A041202 study, researchers compared ibrutinib alone (Ib) or in combination with rituximab (Ib-R) to bendamustine plus rituximab (BR) in untreated, older patients with CLL. The 2-year PFS estimates were 74% in the BR arm, 87% in the Ib arm, and 88% in the Ib-R arm (P less than .001 for BR vs. Ib or Ib-R; N Engl J Med. 2018; 379:2517-28).

In the E1912 trial, researchers compared Ib-R to fludarabine, cyclophosphamide, and rituximab (FCR) in younger, untreated CLL patients. The 3-year PFS was 89.4% with Ib-R and 72.9% with FCR (P less than .001; N Engl J Med. 2019 Aug 1;381:432-43).

Dr. Wierda noted that the E1912 trial also showed superior OS with Ib-R. The 3-year OS rate was 98.8% with Ib-R and 91.5% with FCR (P less than .001). However, there was no significant difference in OS between the treatment arms in the A041202 trial or the iLLUMINATE trial.

“But I would argue that is, in part, because of short follow-up,” Dr. Wierda said. “The trials were all designed to look at progression-free survival, not overall survival. With longer follow-up, we may see differences in overall survival emerging.”

Dr. Wierda went on to say that fixed‐duration treatment with the BCL2 inhibitor venetoclax can improve PFS over CIT.

In the phase 3 CLL14 trial, researchers compared fixed-duration treatment with venetoclax plus obinutuzumab to chlorambucil plus obinutuzumab in previously untreated CLL patients with comorbidities. The estimated PFS at 2 years was 88.2% in the venetoclax group and 64.1% in the chlorambucil group (P less than .001; N Engl J Med. 2019; 380:2225-36).

“[There was] no difference in overall survival,” Dr. Wierda noted. “But, again, I would argue ... that follow-up is relatively limited. We may ultimately see a difference in overall survival.”

Based on these findings, Dr. Wierda made the following treatment recommendations:

• Any CLL patient with del(17p) or TP53 mutation, and older, unfit patients with unmutated IGHV should receive a BTK inhibitor, with or without obinutuzumab.
• All young, fit patients, and older, unfit patients with mutated IGHV should receive a BCL2 inhibitor plus obinutuzumab.

Dr. Wierda also noted that ibrutinib and venetoclax in combination have shown early promise for patients with previously untreated CLL (N Engl J Med. 2019; 380:2095-2103).
 

CIT still has a role as first-line treatment

Dr. Brown suggested that a PFS benefit may not be enough to recommend targeted agents over CIT. For one thing, the PFS benefit doesn’t apply to all patients, as the IGHV-mutated subgroup does equally well with CIT and targeted agents.

Jennifer Smith/MDedge News

In the IGHV-mutated group from the E1912 trial, the 3-year PFS was 88% for patients who received Ib-R and those who received FCR (N Engl J Med. 2019 Aug 1;381:432-43). In the A041202 study, the 2-year PFS among IGHV-mutated patients was 87% in the BR arm, 86% in the Ib arm, and 88% in the Ib-R arm (N Engl J Med. 2018; 379:2517-28).

In the CLL14 trial, PFS rates were similar among IGHV-mutated patients who received chlorambucil plus obinutuzumab and IGHV-mutated or unmutated patients who received venetoclax and obinutuzumab (N Engl J Med. 2019; 380:2225-36).

Dr. Brown also noted that the overall improvement in PFS observed with ibrutinib and venetoclax doesn’t always translate to improved OS.

In the A041202 study, there was no significant difference in OS between the Ib, Ib-R, and BR arms (N Engl J Med. 2018; 379:2517-28). There was no significant difference in OS between the ibrutinib and chlorambucil arms in the iLLUMINATE trial (Lancet Oncol. 2019 Jan;20[1]:43-56). And there was no significant difference in OS between the venetoclax and chlorambucil arms in the CLL14 trial (N Engl J Med. 2019; 380:2225-36).

However, in the RESONATE-2 trial, ibrutinib provided an OS benefit over chlorambucil. The 2-year OS was 95% and 84%, respectively (P = .0145; Haematologica. Sept 2018;103:1502-10). Dr. Brown said the OS advantage in this study was due to the “very poor comparator of chlorambucil and very limited crossover.”

As Dr. Wierda mentioned, the OS rate was higher with Ib-R than with FCR in the E1912 trial. The 3-year OS rate was 98.8% and 91.5%, respectively (P less than .001; N Engl J Med. 2019 Aug 1;381:432-43). Dr. Brown noted, however, that there were few deaths in this study, and many of them “were not clearly related to the disease or its treatment.”

Dr. Brown also pointed out that FCR has been shown to have curative potential in IGHV-mutated CLL in both the FCR300 trial (Blood. 2016 127:303-9) and the CLL8 trial (Blood. 2016 127:208-15).

Another factor to consider is the greater cost of targeted agents. One analysis suggested the per-patient lifetime cost of CLL treatment in the United States will increase from $147,000 to $604,000 as targeted therapies overtake CIT as first-line treatment (J Clin Oncol. 2017 Jan 10;35[2]:166-174).

“Given all of the above, chemoimmunotherapy is going to remain part of the treatment repertoire for CLL,” Dr. Brown said. “It’s our only known potential cure for the fit, mutated patients ... and can also result in prolonged treatment-free intervals for patients who are older. As we manage CLL as a chronic disease over a lifetime, we need to continue to have this in our armamentarium.”

Specifically, Dr. Brown said CIT is appropriate for patients who don’t have del(17p) or mutated TP53. FCR should be given to young, fit patients with IGHV-mutated CLL, and FCR or BR should be given to older patients and young, fit patients with IGHV-unmutated CLL.

Dr. Brown and Dr. Wierda reported financial ties to multiple pharmaceutical companies, including makers of CLL treatments.

[email protected]

SAN FRANCISCO – Positive results with blinatumomab and inotuzumab ozogamicin in the relapsed/refractory setting have prompted trials of these immunotherapies in newly diagnosed B-cell acute lymphoblastic leukemia (B-ALL).

Blinatumomab and inotuzumab have been shown to improve overall survival, compared with chemotherapy, in patients with relapsed/refractory B-ALL. However, most adults with relapsed/refractory B-ALL still die, so the initial therapy patients receive is “critical,” according to Jae Park, MD, of Memorial Sloan Kettering Cancer Center in New York.

“Ideally, we do not want to deal with the relapse,” Dr. Park said. “It’s better to cure the disease the first time ... which is the reason clinical trials are incorporating these agents earlier.”

Dr. Park discussed these points at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.
 

Blinatumomab

Dr. Park cited the phase 3 TOWER trial, which showed that blinatumomab produced better response rates and overall survival compared with standard chemotherapy. The trial enrolled 405 patients with Ph-negative relapsed/refractory B-ALL who were randomized to blinatumomab (n = 271) or chemotherapy (n = 134).

The rate of complete response (CR) with full, partial, or incomplete hematologic recovery was 44% with blinatumomab and 25% with chemotherapy (P less than .001). The median overall survival was 7.7 months and 4.0 months, respectively (P = .01; N Engl J Med 2017; 376:836-47).

Based on these data, researchers decided to test blinatumomab in newly diagnosed, elderly patients (65 years and older) with Ph-negative B-ALL in the phase 2 SWOG 1318 study. The study enrolled 31 patients, and 29 were eligible. Their median age at baseline was 75 years (range 66‐84 years).

The patients received blinatumomab for two to five cycles, followed by 18 months of maintenance with prednisone, vincristine, 6-mercaptopurine, and methotrexate. One patient went on to transplant.

In all, 66% of patients achieved a CR or CR with incomplete count recovery. The estimated overall survival was 79% at 6 months and 65% at 1 year. These results were presented at the 2018 annual meeting of the American Society of Hematology (Blood. 2018;132:33).

Another study of blinatumomab as frontline treatment is the ECOG-E1910 trial. In this phase 3 study, researchers are testing chemotherapy, with or without blinatumomab, in adults (aged 30-70 years) with newly diagnosed, BCR-ABL-negative B-ALL. Results from this study are not yet available.
 

Inotuzumab ozogamicin

Dr. Park also discussed the INOVATE trial, in which inotuzumab ozogamicin bested standard chemotherapy. The trial enrolled patients with Ph-positive or negative, relapsed/refractory B-ALL.

The patients were randomized to inotuzumab (n = 141) or investigator’s choice of chemotherapy (n = 138). Some patients, 41% in the inotuzumab arm and 11% in the chemotherapy arm, went on to transplant.

The CR rate was 80.7% in the inotuzumab arm and 29.4% in the chemotherapy arm (P less than .001). The median progression-free survival was 5 months and 1.8 months, respectively (P less than .001). The median overall survival was 7.7 months and 6.7 months, respectively (P = .04; N Engl J Med 2016; 375:740-53).

Based on these results, researchers are testing inotuzumab as frontline therapy in young adults (aged 18-39 years) with CD22-positive, Ph-negative B-ALL. In the phase 3 A041501 trial, patients are receiving inotuzumab after the first and second courses of treatment with the CALGB 10403 chemotherapy regimen. Results from this trial are not yet available.

Dr. Park reported relationships with Allogene Therapeutics, Amgen, AstraZeneca, Incyte, Kite Pharma, Novartis, and Takeda.

[email protected]

SAN FRANCISCO – Positive results with blinatumomab and inotuzumab ozogamicin in the relapsed/refractory setting have prompted trials of these immunotherapies in newly diagnosed B-cell acute lymphoblastic leukemia (B-ALL).

Blinatumomab and inotuzumab have been shown to improve overall survival, compared with chemotherapy, in patients with relapsed/refractory B-ALL. However, most adults with relapsed/refractory B-ALL still die, so the initial therapy patients receive is “critical,” according to Jae Park, MD, of Memorial Sloan Kettering Cancer Center in New York.

“Ideally, we do not want to deal with the relapse,” Dr. Park said. “It’s better to cure the disease the first time ... which is the reason clinical trials are incorporating these agents earlier.”

Dr. Park discussed these points at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.
 

Blinatumomab

Dr. Park cited the phase 3 TOWER trial, which showed that blinatumomab produced better response rates and overall survival compared with standard chemotherapy. The trial enrolled 405 patients with Ph-negative relapsed/refractory B-ALL who were randomized to blinatumomab (n = 271) or chemotherapy (n = 134).

The rate of complete response (CR) with full, partial, or incomplete hematologic recovery was 44% with blinatumomab and 25% with chemotherapy (P less than .001). The median overall survival was 7.7 months and 4.0 months, respectively (P = .01; N Engl J Med 2017; 376:836-47).

Based on these data, researchers decided to test blinatumomab in newly diagnosed, elderly patients (65 years and older) with Ph-negative B-ALL in the phase 2 SWOG 1318 study. The study enrolled 31 patients, and 29 were eligible. Their median age at baseline was 75 years (range 66‐84 years).

The patients received blinatumomab for two to five cycles, followed by 18 months of maintenance with prednisone, vincristine, 6-mercaptopurine, and methotrexate. One patient went on to transplant.

In all, 66% of patients achieved a CR or CR with incomplete count recovery. The estimated overall survival was 79% at 6 months and 65% at 1 year. These results were presented at the 2018 annual meeting of the American Society of Hematology (Blood. 2018;132:33).

Another study of blinatumomab as frontline treatment is the ECOG-E1910 trial. In this phase 3 study, researchers are testing chemotherapy, with or without blinatumomab, in adults (aged 30-70 years) with newly diagnosed, BCR-ABL-negative B-ALL. Results from this study are not yet available.
 

Inotuzumab ozogamicin

Dr. Park also discussed the INOVATE trial, in which inotuzumab ozogamicin bested standard chemotherapy. The trial enrolled patients with Ph-positive or negative, relapsed/refractory B-ALL.

The patients were randomized to inotuzumab (n = 141) or investigator’s choice of chemotherapy (n = 138). Some patients, 41% in the inotuzumab arm and 11% in the chemotherapy arm, went on to transplant.

The CR rate was 80.7% in the inotuzumab arm and 29.4% in the chemotherapy arm (P less than .001). The median progression-free survival was 5 months and 1.8 months, respectively (P less than .001). The median overall survival was 7.7 months and 6.7 months, respectively (P = .04; N Engl J Med 2016; 375:740-53).

Based on these results, researchers are testing inotuzumab as frontline therapy in young adults (aged 18-39 years) with CD22-positive, Ph-negative B-ALL. In the phase 3 A041501 trial, patients are receiving inotuzumab after the first and second courses of treatment with the CALGB 10403 chemotherapy regimen. Results from this trial are not yet available.

Dr. Park reported relationships with Allogene Therapeutics, Amgen, AstraZeneca, Incyte, Kite Pharma, Novartis, and Takeda.

[email protected]

SAN FRANCISCO – Positive results with blinatumomab and inotuzumab ozogamicin in the relapsed/refractory setting have prompted trials of these immunotherapies in newly diagnosed B-cell acute lymphoblastic leukemia (B-ALL).

Blinatumomab and inotuzumab have been shown to improve overall survival, compared with chemotherapy, in patients with relapsed/refractory B-ALL. However, most adults with relapsed/refractory B-ALL still die, so the initial therapy patients receive is “critical,” according to Jae Park, MD, of Memorial Sloan Kettering Cancer Center in New York.

“Ideally, we do not want to deal with the relapse,” Dr. Park said. “It’s better to cure the disease the first time ... which is the reason clinical trials are incorporating these agents earlier.”

Dr. Park discussed these points at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.
 

Blinatumomab

Dr. Park cited the phase 3 TOWER trial, which showed that blinatumomab produced better response rates and overall survival compared with standard chemotherapy. The trial enrolled 405 patients with Ph-negative relapsed/refractory B-ALL who were randomized to blinatumomab (n = 271) or chemotherapy (n = 134).

The rate of complete response (CR) with full, partial, or incomplete hematologic recovery was 44% with blinatumomab and 25% with chemotherapy (P less than .001). The median overall survival was 7.7 months and 4.0 months, respectively (P = .01; N Engl J Med 2017; 376:836-47).

Based on these data, researchers decided to test blinatumomab in newly diagnosed, elderly patients (65 years and older) with Ph-negative B-ALL in the phase 2 SWOG 1318 study. The study enrolled 31 patients, and 29 were eligible. Their median age at baseline was 75 years (range 66‐84 years).

The patients received blinatumomab for two to five cycles, followed by 18 months of maintenance with prednisone, vincristine, 6-mercaptopurine, and methotrexate. One patient went on to transplant.

In all, 66% of patients achieved a CR or CR with incomplete count recovery. The estimated overall survival was 79% at 6 months and 65% at 1 year. These results were presented at the 2018 annual meeting of the American Society of Hematology (Blood. 2018;132:33).

Another study of blinatumomab as frontline treatment is the ECOG-E1910 trial. In this phase 3 study, researchers are testing chemotherapy, with or without blinatumomab, in adults (aged 30-70 years) with newly diagnosed, BCR-ABL-negative B-ALL. Results from this study are not yet available.
 

Inotuzumab ozogamicin

Dr. Park also discussed the INOVATE trial, in which inotuzumab ozogamicin bested standard chemotherapy. The trial enrolled patients with Ph-positive or negative, relapsed/refractory B-ALL.

The patients were randomized to inotuzumab (n = 141) or investigator’s choice of chemotherapy (n = 138). Some patients, 41% in the inotuzumab arm and 11% in the chemotherapy arm, went on to transplant.

The CR rate was 80.7% in the inotuzumab arm and 29.4% in the chemotherapy arm (P less than .001). The median progression-free survival was 5 months and 1.8 months, respectively (P less than .001). The median overall survival was 7.7 months and 6.7 months, respectively (P = .04; N Engl J Med 2016; 375:740-53).

Based on these results, researchers are testing inotuzumab as frontline therapy in young adults (aged 18-39 years) with CD22-positive, Ph-negative B-ALL. In the phase 3 A041501 trial, patients are receiving inotuzumab after the first and second courses of treatment with the CALGB 10403 chemotherapy regimen. Results from this trial are not yet available.

Dr. Park reported relationships with Allogene Therapeutics, Amgen, AstraZeneca, Incyte, Kite Pharma, Novartis, and Takeda.

[email protected]

EDINBURGH – Lenalidomide maintenance therapy after chemoimmunotherapy in high-risk chronic lymphocytic leukemia (CLL) improved progression- and event-free survival, but not overall survival, and was associated with three unexpected cases of B-cell acute lymphoblastic leukemia (B-ALL), according to 4-year follow-up in the German, phase 3 CLLM1 study.

Given these findings, and in particular the B-ALL cases, lenalidomide cannot be generally recommended as maintenance therapy in high-risk CLL, Moritz Fürstenau, MD, of the University of Cologne, reported in a poster at the International Workshop on Chronic Lymphocytic Leukemia.

At a median follow-up of 47.6 months, median progression-free survival (PFS) by investigator assessment was 54.7 months in 60 patients randomized to receive lenalidomide maintenance therapy, compared with 23.2 months for 29 who received placebo (hazard ratio, 0.22), and median event-free survival (EFS) was 46.2 months vs. 14.6 months in the groups, respectively (hazard ratio, 0.24), Dr. Fürstenau said during an oral poster presentation at the conference.

“So ... after 4 years of observation, we still see improvement in PFS, EFS, and time to next treatment,” he said, also noting that minimal residual disease (MRD) negativity was achieved by eight patients in the lenalidomide group, and in none of the patients in the placebo group.

However, overall survival was 79% and 87% in the lenalidomide and placebo groups, respectively (HR, 1.53). In total, 12 patients died, including 9 in the lenalidomide group from fatal infections, concomitant disease, CLL progression, or unknown causes. Three patients in the placebo group died from CLL progression or fatal infection.

In the lenalidomide group, hematological and solid tumor second primary malignancies were reported in three and four patients, respectively (5% and 7%), compared with zero and two patients, respectively (0% and 7%), in the placebo group.

The CLLM1 study of the German CLL Study Group evaluated maintenance with lenalidomide vs. placebo in patients with high risk of progression after first-line chemoimmunotherapy. Previously reported results also favored lenalidomide maintenance for PFS, but not OS, Dr. Fürstenau said, adding that the study was unblinded at a median follow-up of 17.9 months, and in November 2017 treatment was stopped when two cases of B-ALL were observed. A third case was reported in 2018.

The current analysis includes data available through December 2018, and the findings warrant further investigation to analyze the unexpectedly high incidence of B-ALL, he said.

The CLLM1 study was funded by Celgene.

[email protected]

EDINBURGH – Lenalidomide maintenance therapy after chemoimmunotherapy in high-risk chronic lymphocytic leukemia (CLL) improved progression- and event-free survival, but not overall survival, and was associated with three unexpected cases of B-cell acute lymphoblastic leukemia (B-ALL), according to 4-year follow-up in the German, phase 3 CLLM1 study.

Given these findings, and in particular the B-ALL cases, lenalidomide cannot be generally recommended as maintenance therapy in high-risk CLL, Moritz Fürstenau, MD, of the University of Cologne, reported in a poster at the International Workshop on Chronic Lymphocytic Leukemia.

At a median follow-up of 47.6 months, median progression-free survival (PFS) by investigator assessment was 54.7 months in 60 patients randomized to receive lenalidomide maintenance therapy, compared with 23.2 months for 29 who received placebo (hazard ratio, 0.22), and median event-free survival (EFS) was 46.2 months vs. 14.6 months in the groups, respectively (hazard ratio, 0.24), Dr. Fürstenau said during an oral poster presentation at the conference.

“So ... after 4 years of observation, we still see improvement in PFS, EFS, and time to next treatment,” he said, also noting that minimal residual disease (MRD) negativity was achieved by eight patients in the lenalidomide group, and in none of the patients in the placebo group.

However, overall survival was 79% and 87% in the lenalidomide and placebo groups, respectively (HR, 1.53). In total, 12 patients died, including 9 in the lenalidomide group from fatal infections, concomitant disease, CLL progression, or unknown causes. Three patients in the placebo group died from CLL progression or fatal infection.

In the lenalidomide group, hematological and solid tumor second primary malignancies were reported in three and four patients, respectively (5% and 7%), compared with zero and two patients, respectively (0% and 7%), in the placebo group.

The CLLM1 study of the German CLL Study Group evaluated maintenance with lenalidomide vs. placebo in patients with high risk of progression after first-line chemoimmunotherapy. Previously reported results also favored lenalidomide maintenance for PFS, but not OS, Dr. Fürstenau said, adding that the study was unblinded at a median follow-up of 17.9 months, and in November 2017 treatment was stopped when two cases of B-ALL were observed. A third case was reported in 2018.

The current analysis includes data available through December 2018, and the findings warrant further investigation to analyze the unexpectedly high incidence of B-ALL, he said.

The CLLM1 study was funded by Celgene.

[email protected]

EDINBURGH – Lenalidomide maintenance therapy after chemoimmunotherapy in high-risk chronic lymphocytic leukemia (CLL) improved progression- and event-free survival, but not overall survival, and was associated with three unexpected cases of B-cell acute lymphoblastic leukemia (B-ALL), according to 4-year follow-up in the German, phase 3 CLLM1 study.

Given these findings, and in particular the B-ALL cases, lenalidomide cannot be generally recommended as maintenance therapy in high-risk CLL, Moritz Fürstenau, MD, of the University of Cologne, reported in a poster at the International Workshop on Chronic Lymphocytic Leukemia.

At a median follow-up of 47.6 months, median progression-free survival (PFS) by investigator assessment was 54.7 months in 60 patients randomized to receive lenalidomide maintenance therapy, compared with 23.2 months for 29 who received placebo (hazard ratio, 0.22), and median event-free survival (EFS) was 46.2 months vs. 14.6 months in the groups, respectively (hazard ratio, 0.24), Dr. Fürstenau said during an oral poster presentation at the conference.

“So ... after 4 years of observation, we still see improvement in PFS, EFS, and time to next treatment,” he said, also noting that minimal residual disease (MRD) negativity was achieved by eight patients in the lenalidomide group, and in none of the patients in the placebo group.

However, overall survival was 79% and 87% in the lenalidomide and placebo groups, respectively (HR, 1.53). In total, 12 patients died, including 9 in the lenalidomide group from fatal infections, concomitant disease, CLL progression, or unknown causes. Three patients in the placebo group died from CLL progression or fatal infection.

In the lenalidomide group, hematological and solid tumor second primary malignancies were reported in three and four patients, respectively (5% and 7%), compared with zero and two patients, respectively (0% and 7%), in the placebo group.

The CLLM1 study of the German CLL Study Group evaluated maintenance with lenalidomide vs. placebo in patients with high risk of progression after first-line chemoimmunotherapy. Previously reported results also favored lenalidomide maintenance for PFS, but not OS, Dr. Fürstenau said, adding that the study was unblinded at a median follow-up of 17.9 months, and in November 2017 treatment was stopped when two cases of B-ALL were observed. A third case was reported in 2018.

The current analysis includes data available through December 2018, and the findings warrant further investigation to analyze the unexpectedly high incidence of B-ALL, he said.

The CLLM1 study was funded by Celgene.

[email protected]

EDINBURGH – Treatment induction with obinutuzumab and ibrutinib followed by a minimal residual disease (MRD)–driven treatment strategy in patients with chronic lymphocytic leukemia (CLL) yields a high long-term complete response rate and prolonged progression-free and overall survival, according to findings from the phase 2 ICLL-07 trial.

The intent-to-treat (ITT) complete response rate at 16 months in 135 patients who were treated with this strategy was 62%, Anne-Sophie Michallet, MD, reported at the International Workshop on Chronic Lymphocytic Leukemia.

Patients in the multicenter, open-label trial conducted by the French Innovative Leukemia Organization (FILO) were previously untreated, medically fit patients with CLL and no 17p deletion. They were enrolled between November 2015 and May 2017 to receive eight 1,000 mg IV doses of obinutuzumab over six 4-week cycles along with oral Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib at a dose of 420 mg daily for 9 months.

Ten patients (7.7%) achieved complete response with bone marrow MRD less than 0.01% (undetectable) at 9 months and, by study protocol, continued on only the ibrutinib for 6 additional months. The remaining 120 evaluable patients received four 4-week cycles of fludarabine/cyclophosphamide along with the obinutuzumab and ibrutinib for 6 additional months, explained Dr. Michallet of Centre Léon Bérard, Lyon, France.

The ITT rate at 16 months – the primary endpoint of the study – was achieved with no more than four cycles of fludarabine/cyclophosphamide and obinutuzumab, and exceeded the primary objective of demonstrating a 30% or higher rate of complete response with bone marrow MRD less than 0.01% at the month 16 ITT analysis, she said.

“The ... strategy yielded an overall response rate of 100%, a complete response rate, according to iwCLL [criteria], of 73%, a bone marrow MRD–undetectable rate of 79% [in the ITT population],” she said, adding that the primary objective was achieved with a complete response with a peripheral blood and bone marrow MRD–undetectable rate of 62%.

Response assessments at months 9 and 16 involved whole-body computed tomography scans with tumor measurements and bone marrow trephine biopsy for patients in clinical complete response. MRD testing was performed by eight-color flow cytometry in both peripheral blood and bone marrow.

After month 16, response was clinically assessed every 3 months, and peripheral blood MRD was assessed every 6 months until month 40.

“With a median follow-up of 26.3 months, the 2-year progression-free survival and overall survival were, respectively, 97% and 97.5%,” Dr. Michallet said, noting that the longitudinal follow-up of peripheral blood MRD in the entire cohort showed durability of a deep response. The rate of peripheral blood MRD less than 0.01% at 22 months was 77% in the 10 patients who received only ibrutinib after the 9-month assessment, and 93% in those who received fludarabine/cyclophosphamide after the 9-month assessment.

In patients with immunoglobulin heavy gene variable (IGHV) mutations, the rate of peripheral blood MRD less than 0.01% at month 22 was 96%, and in those without IGHV mutations, the rate was 77%, she noted.

The findings demonstrate that the approach has merit in medically fit, treatment-naive patients with CLL and no 17p deletion, she said, explaining that the fixed-duration, MRD-driven strategy used in this study was developed to “avoid or at least reduce chemotherapy exposure” in the first-line treatment of such patients.

Indeed, the approach was associated with “a high [complete response] rate, a high level of undetectable bone marrow MRD, an acceptable safety profile, and a sustained MRD negativity rate at 12 months after the end of the treatment,” she said.

“This highly effective strategy combining a BTK inhibitor and abbreviated immunochemotherapy deserves further investigation with randomized trials,” she concluded.

ICLL-07 FILO was funded by Roche and Janssen. Dr. Michallet reported having no disclosures.

[email protected]

EDINBURGH – Treatment induction with obinutuzumab and ibrutinib followed by a minimal residual disease (MRD)–driven treatment strategy in patients with chronic lymphocytic leukemia (CLL) yields a high long-term complete response rate and prolonged progression-free and overall survival, according to findings from the phase 2 ICLL-07 trial.

The intent-to-treat (ITT) complete response rate at 16 months in 135 patients who were treated with this strategy was 62%, Anne-Sophie Michallet, MD, reported at the International Workshop on Chronic Lymphocytic Leukemia.

Patients in the multicenter, open-label trial conducted by the French Innovative Leukemia Organization (FILO) were previously untreated, medically fit patients with CLL and no 17p deletion. They were enrolled between November 2015 and May 2017 to receive eight 1,000 mg IV doses of obinutuzumab over six 4-week cycles along with oral Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib at a dose of 420 mg daily for 9 months.

Ten patients (7.7%) achieved complete response with bone marrow MRD less than 0.01% (undetectable) at 9 months and, by study protocol, continued on only the ibrutinib for 6 additional months. The remaining 120 evaluable patients received four 4-week cycles of fludarabine/cyclophosphamide along with the obinutuzumab and ibrutinib for 6 additional months, explained Dr. Michallet of Centre Léon Bérard, Lyon, France.

The ITT rate at 16 months – the primary endpoint of the study – was achieved with no more than four cycles of fludarabine/cyclophosphamide and obinutuzumab, and exceeded the primary objective of demonstrating a 30% or higher rate of complete response with bone marrow MRD less than 0.01% at the month 16 ITT analysis, she said.

“The ... strategy yielded an overall response rate of 100%, a complete response rate, according to iwCLL [criteria], of 73%, a bone marrow MRD–undetectable rate of 79% [in the ITT population],” she said, adding that the primary objective was achieved with a complete response with a peripheral blood and bone marrow MRD–undetectable rate of 62%.

Response assessments at months 9 and 16 involved whole-body computed tomography scans with tumor measurements and bone marrow trephine biopsy for patients in clinical complete response. MRD testing was performed by eight-color flow cytometry in both peripheral blood and bone marrow.

After month 16, response was clinically assessed every 3 months, and peripheral blood MRD was assessed every 6 months until month 40.

“With a median follow-up of 26.3 months, the 2-year progression-free survival and overall survival were, respectively, 97% and 97.5%,” Dr. Michallet said, noting that the longitudinal follow-up of peripheral blood MRD in the entire cohort showed durability of a deep response. The rate of peripheral blood MRD less than 0.01% at 22 months was 77% in the 10 patients who received only ibrutinib after the 9-month assessment, and 93% in those who received fludarabine/cyclophosphamide after the 9-month assessment.

In patients with immunoglobulin heavy gene variable (IGHV) mutations, the rate of peripheral blood MRD less than 0.01% at month 22 was 96%, and in those without IGHV mutations, the rate was 77%, she noted.

The findings demonstrate that the approach has merit in medically fit, treatment-naive patients with CLL and no 17p deletion, she said, explaining that the fixed-duration, MRD-driven strategy used in this study was developed to “avoid or at least reduce chemotherapy exposure” in the first-line treatment of such patients.

Indeed, the approach was associated with “a high [complete response] rate, a high level of undetectable bone marrow MRD, an acceptable safety profile, and a sustained MRD negativity rate at 12 months after the end of the treatment,” she said.

“This highly effective strategy combining a BTK inhibitor and abbreviated immunochemotherapy deserves further investigation with randomized trials,” she concluded.

ICLL-07 FILO was funded by Roche and Janssen. Dr. Michallet reported having no disclosures.

[email protected]

EDINBURGH – Treatment induction with obinutuzumab and ibrutinib followed by a minimal residual disease (MRD)–driven treatment strategy in patients with chronic lymphocytic leukemia (CLL) yields a high long-term complete response rate and prolonged progression-free and overall survival, according to findings from the phase 2 ICLL-07 trial.

The intent-to-treat (ITT) complete response rate at 16 months in 135 patients who were treated with this strategy was 62%, Anne-Sophie Michallet, MD, reported at the International Workshop on Chronic Lymphocytic Leukemia.

Patients in the multicenter, open-label trial conducted by the French Innovative Leukemia Organization (FILO) were previously untreated, medically fit patients with CLL and no 17p deletion. They were enrolled between November 2015 and May 2017 to receive eight 1,000 mg IV doses of obinutuzumab over six 4-week cycles along with oral Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib at a dose of 420 mg daily for 9 months.

Ten patients (7.7%) achieved complete response with bone marrow MRD less than 0.01% (undetectable) at 9 months and, by study protocol, continued on only the ibrutinib for 6 additional months. The remaining 120 evaluable patients received four 4-week cycles of fludarabine/cyclophosphamide along with the obinutuzumab and ibrutinib for 6 additional months, explained Dr. Michallet of Centre Léon Bérard, Lyon, France.

The ITT rate at 16 months – the primary endpoint of the study – was achieved with no more than four cycles of fludarabine/cyclophosphamide and obinutuzumab, and exceeded the primary objective of demonstrating a 30% or higher rate of complete response with bone marrow MRD less than 0.01% at the month 16 ITT analysis, she said.

“The ... strategy yielded an overall response rate of 100%, a complete response rate, according to iwCLL [criteria], of 73%, a bone marrow MRD–undetectable rate of 79% [in the ITT population],” she said, adding that the primary objective was achieved with a complete response with a peripheral blood and bone marrow MRD–undetectable rate of 62%.

Response assessments at months 9 and 16 involved whole-body computed tomography scans with tumor measurements and bone marrow trephine biopsy for patients in clinical complete response. MRD testing was performed by eight-color flow cytometry in both peripheral blood and bone marrow.

After month 16, response was clinically assessed every 3 months, and peripheral blood MRD was assessed every 6 months until month 40.

“With a median follow-up of 26.3 months, the 2-year progression-free survival and overall survival were, respectively, 97% and 97.5%,” Dr. Michallet said, noting that the longitudinal follow-up of peripheral blood MRD in the entire cohort showed durability of a deep response. The rate of peripheral blood MRD less than 0.01% at 22 months was 77% in the 10 patients who received only ibrutinib after the 9-month assessment, and 93% in those who received fludarabine/cyclophosphamide after the 9-month assessment.

In patients with immunoglobulin heavy gene variable (IGHV) mutations, the rate of peripheral blood MRD less than 0.01% at month 22 was 96%, and in those without IGHV mutations, the rate was 77%, she noted.

The findings demonstrate that the approach has merit in medically fit, treatment-naive patients with CLL and no 17p deletion, she said, explaining that the fixed-duration, MRD-driven strategy used in this study was developed to “avoid or at least reduce chemotherapy exposure” in the first-line treatment of such patients.

Indeed, the approach was associated with “a high [complete response] rate, a high level of undetectable bone marrow MRD, an acceptable safety profile, and a sustained MRD negativity rate at 12 months after the end of the treatment,” she said.

“This highly effective strategy combining a BTK inhibitor and abbreviated immunochemotherapy deserves further investigation with randomized trials,” she concluded.

ICLL-07 FILO was funded by Roche and Janssen. Dr. Michallet reported having no disclosures.

[email protected]

New research suggests several factors are associated with failure to discontinue immune suppression after allogeneic hematopoietic cell transplant (HCT).

Patients older than 50 years, those with advanced stage disease, patients with a mismatched unrelated donor, and those who received peripheral blood stem cells from an unrelated donor were less likely to discontinue immune suppression successfully, Joseph Pidala, MD, PhD, of Moffitt Cancer Center in Tampa, Fla., and colleagues reported in JAMA Oncology.

The researchers analyzed data from 827 patients in two national Blood and Marrow Transplant Clinical Trial Network studies (NCT00075816 and NCT00406393). These randomized, phase 3 trials enrolled patients with hematologic malignancies who received myeloablative conditioning before allogeneic HCT.

The patients’ median age at HCT was 44 years (range, less than 1 to 67 years), and 55.1% were male. The median follow-up was 72 months (range, 11-124 months).

At 5 years, 20% of patients (n = 168) had successfully discontinued immune suppression and were still alive. A total of 342 patients (41.4%) were able to stop immune suppression, but 127 of them had to resume it after developing graft-versus-host disease (GVHD). There were an additional 47 patients who died or relapsed after stopping immune suppression.

The researchers identified several factors that were significantly associated with lower odds of discontinuing immune suppression and being free of GVHD, including:
 

• Being older than 50 years versus younger than 30 years (adjusted odds ratio [aOR], 0.27; 99% confidence interval [CI], 0.14-0.50; P less than .001).
• Having a mismatched unrelated donor versus having a matched sibling (aOR, 0.37; 99% CI, 0.14-0.97; P = .008).
• Receiving peripheral blood stem cells versus bone marrow, from unrelated donors only (aOR, 0.46; 99% CI, 0.26-0.82; P less than .001).
• Having advanced stage disease versus early disease (aOR, 0.45; 99%CI, 0.23-0.86; P = .002).

The researchers also found that discontinuing immune suppression was not significantly associated with a decreased risk of relapse, with a hazard ratio (HR) of 1.95 (99% CI, 0.88-4.31; P = .03).

There was no significant association between acute GVHD–related variables and discontinuation of immune suppression. However, there were a few factors significantly associated with a lower likelihood of discontinuation after chronic GVHD, including:
 

• Current skin involvement (HR, 0.33; 99% CI, 0.14-0.80; P = .001).
• Unrelated well-matched donor versus matched sibling donor (HR, 0.29; 99% CI, 0.10-0.79; P = .001).
• Unrelated mismatched donor versus matched sibling donor (HR, 0.17; 99% CI, 0.03-0.95; P = .008).

In total, 127 patients had to resume immune suppression because of GVHD. Such failed attempts at discontinuing immune suppression were associated with receiving peripheral blood stem cells from an unrelated donor versus bone marrow from an unrelated donor, with an HR of 2.62 (99% CI, 1.30-5.29; P less than .001).

A history of acute or chronic GVHD was associated with failure to discontinue immune suppression, the researchers noted.

Lastly, the researchers developed dynamic prediction models for the probability of freedom from immune suppression and GVHD at 1, 3, and 5 years in the future. The team found that graft type, donor type, age, state history, and timing of immune suppression discontinuation were all associated with the likelihood of being free from immune suppression and GVHD at all three time points. Disease risk was only associated with freedom from immune suppression and GVHD at the 1-year mark.

The researchers said their findings must be validated in an independent cohort of patients and, after that, should be tested in a prospective trial.

The current study was funded by the National Heart Lung and Blood Institute. Two of the researchers reported relationships with more than 30 pharmaceutical companies.

[email protected]

SOURCE: Pidala J et al. JAMA Oncol. 2019 Sep 26. doi: 10.1001/jamaoncol.2019.2974.

New research suggests several factors are associated with failure to discontinue immune suppression after allogeneic hematopoietic cell transplant (HCT).

Patients older than 50 years, those with advanced stage disease, patients with a mismatched unrelated donor, and those who received peripheral blood stem cells from an unrelated donor were less likely to discontinue immune suppression successfully, Joseph Pidala, MD, PhD, of Moffitt Cancer Center in Tampa, Fla., and colleagues reported in JAMA Oncology.

The researchers analyzed data from 827 patients in two national Blood and Marrow Transplant Clinical Trial Network studies (NCT00075816 and NCT00406393). These randomized, phase 3 trials enrolled patients with hematologic malignancies who received myeloablative conditioning before allogeneic HCT.

The patients’ median age at HCT was 44 years (range, less than 1 to 67 years), and 55.1% were male. The median follow-up was 72 months (range, 11-124 months).

At 5 years, 20% of patients (n = 168) had successfully discontinued immune suppression and were still alive. A total of 342 patients (41.4%) were able to stop immune suppression, but 127 of them had to resume it after developing graft-versus-host disease (GVHD). There were an additional 47 patients who died or relapsed after stopping immune suppression.

The researchers identified several factors that were significantly associated with lower odds of discontinuing immune suppression and being free of GVHD, including:
 

• Being older than 50 years versus younger than 30 years (adjusted odds ratio [aOR], 0.27; 99% confidence interval [CI], 0.14-0.50; P less than .001).
• Having a mismatched unrelated donor versus having a matched sibling (aOR, 0.37; 99% CI, 0.14-0.97; P = .008).
• Receiving peripheral blood stem cells versus bone marrow, from unrelated donors only (aOR, 0.46; 99% CI, 0.26-0.82; P less than .001).
• Having advanced stage disease versus early disease (aOR, 0.45; 99%CI, 0.23-0.86; P = .002).

The researchers also found that discontinuing immune suppression was not significantly associated with a decreased risk of relapse, with a hazard ratio (HR) of 1.95 (99% CI, 0.88-4.31; P = .03).

There was no significant association between acute GVHD–related variables and discontinuation of immune suppression. However, there were a few factors significantly associated with a lower likelihood of discontinuation after chronic GVHD, including:
 

• Current skin involvement (HR, 0.33; 99% CI, 0.14-0.80; P = .001).
• Unrelated well-matched donor versus matched sibling donor (HR, 0.29; 99% CI, 0.10-0.79; P = .001).
• Unrelated mismatched donor versus matched sibling donor (HR, 0.17; 99% CI, 0.03-0.95; P = .008).

In total, 127 patients had to resume immune suppression because of GVHD. Such failed attempts at discontinuing immune suppression were associated with receiving peripheral blood stem cells from an unrelated donor versus bone marrow from an unrelated donor, with an HR of 2.62 (99% CI, 1.30-5.29; P less than .001).

A history of acute or chronic GVHD was associated with failure to discontinue immune suppression, the researchers noted.

Lastly, the researchers developed dynamic prediction models for the probability of freedom from immune suppression and GVHD at 1, 3, and 5 years in the future. The team found that graft type, donor type, age, state history, and timing of immune suppression discontinuation were all associated with the likelihood of being free from immune suppression and GVHD at all three time points. Disease risk was only associated with freedom from immune suppression and GVHD at the 1-year mark.

The researchers said their findings must be validated in an independent cohort of patients and, after that, should be tested in a prospective trial.

The current study was funded by the National Heart Lung and Blood Institute. Two of the researchers reported relationships with more than 30 pharmaceutical companies.

[email protected]

SOURCE: Pidala J et al. JAMA Oncol. 2019 Sep 26. doi: 10.1001/jamaoncol.2019.2974.

New research suggests several factors are associated with failure to discontinue immune suppression after allogeneic hematopoietic cell transplant (HCT).

Patients older than 50 years, those with advanced stage disease, patients with a mismatched unrelated donor, and those who received peripheral blood stem cells from an unrelated donor were less likely to discontinue immune suppression successfully, Joseph Pidala, MD, PhD, of Moffitt Cancer Center in Tampa, Fla., and colleagues reported in JAMA Oncology.

The researchers analyzed data from 827 patients in two national Blood and Marrow Transplant Clinical Trial Network studies (NCT00075816 and NCT00406393). These randomized, phase 3 trials enrolled patients with hematologic malignancies who received myeloablative conditioning before allogeneic HCT.

The patients’ median age at HCT was 44 years (range, less than 1 to 67 years), and 55.1% were male. The median follow-up was 72 months (range, 11-124 months).

At 5 years, 20% of patients (n = 168) had successfully discontinued immune suppression and were still alive. A total of 342 patients (41.4%) were able to stop immune suppression, but 127 of them had to resume it after developing graft-versus-host disease (GVHD). There were an additional 47 patients who died or relapsed after stopping immune suppression.

The researchers identified several factors that were significantly associated with lower odds of discontinuing immune suppression and being free of GVHD, including:
 

• Being older than 50 years versus younger than 30 years (adjusted odds ratio [aOR], 0.27; 99% confidence interval [CI], 0.14-0.50; P less than .001).
• Having a mismatched unrelated donor versus having a matched sibling (aOR, 0.37; 99% CI, 0.14-0.97; P = .008).
• Receiving peripheral blood stem cells versus bone marrow, from unrelated donors only (aOR, 0.46; 99% CI, 0.26-0.82; P less than .001).
• Having advanced stage disease versus early disease (aOR, 0.45; 99%CI, 0.23-0.86; P = .002).

The researchers also found that discontinuing immune suppression was not significantly associated with a decreased risk of relapse, with a hazard ratio (HR) of 1.95 (99% CI, 0.88-4.31; P = .03).

There was no significant association between acute GVHD–related variables and discontinuation of immune suppression. However, there were a few factors significantly associated with a lower likelihood of discontinuation after chronic GVHD, including:
 

• Current skin involvement (HR, 0.33; 99% CI, 0.14-0.80; P = .001).
• Unrelated well-matched donor versus matched sibling donor (HR, 0.29; 99% CI, 0.10-0.79; P = .001).
• Unrelated mismatched donor versus matched sibling donor (HR, 0.17; 99% CI, 0.03-0.95; P = .008).

In total, 127 patients had to resume immune suppression because of GVHD. Such failed attempts at discontinuing immune suppression were associated with receiving peripheral blood stem cells from an unrelated donor versus bone marrow from an unrelated donor, with an HR of 2.62 (99% CI, 1.30-5.29; P less than .001).

A history of acute or chronic GVHD was associated with failure to discontinue immune suppression, the researchers noted.

Lastly, the researchers developed dynamic prediction models for the probability of freedom from immune suppression and GVHD at 1, 3, and 5 years in the future. The team found that graft type, donor type, age, state history, and timing of immune suppression discontinuation were all associated with the likelihood of being free from immune suppression and GVHD at all three time points. Disease risk was only associated with freedom from immune suppression and GVHD at the 1-year mark.

The researchers said their findings must be validated in an independent cohort of patients and, after that, should be tested in a prospective trial.

The current study was funded by the National Heart Lung and Blood Institute. Two of the researchers reported relationships with more than 30 pharmaceutical companies.

[email protected]

SOURCE: Pidala J et al. JAMA Oncol. 2019 Sep 26. doi: 10.1001/jamaoncol.2019.2974.

EDINBURGH – Consolidation therapy with obinutuzumab after chemoimmunotherapy for B-cell chronic lymphocytic leukemia (B-CLL) was highly effective for eradicating minimal residual disease (MRD) within 6 months following randomization in the seamless phase 2/3 GALACTIC trial.

Of 14 patients who were MRD positive after chemoimmunotherapy and randomized to consolidation with the type II monoclonal antibody targeting the CD20 antigen, 10 achieved MRD negativity in the bone marrow by 6 months, and 13 achieved MRD negativity in the peripheral blood by 6 months, Talha Munir, MD, reported at the International Workshop on Chronic Lymphocytic Leukemia.

“And that translated into [progression-free survival] improvement in the consolidation arm,” said Dr. Munir of St. James’s University, Leeds, England.

The median progression-free survival in that arm was not reached, whereas progression-free survival in 15 MRD-positive patients randomized to the nonconsolidation arm was 16.6 months, he said.

Further, no difference was seen in median progression-free survival, overall survival, or MRD duration between the consolidation arm and 19 patients who were not randomized because of MRD negativity after chemoimmunotherapy, he noted.

Achieving MRD negativity in CLL confers a survival advantage, and obinutuzumab has shown greater efficacy with respect to MRD in CLL when compared with previous anti-CD20 antibodies, and it is less immune suppressive than the anti-CD52 antibody alemtuzumab, he explained.

The GALACTIC trial was designed to assess the safety and efficacy of obinutuzumab consolidation for eradicating MRD and whether its effects would prolong progression-free survival in patients with B-CLL who recently responded to chemoimmunotherapy. Those achieving complete response or partial response at 3-24 months after chemoimmunotherapy, and who remained MRD-positive, were eligible for randomization.

The planned sample size was 188 patients, but the trial was closed early in February 2017 because of poor recruitment; a total of 48 patients were enrolled, including the 19 nonrandomized, MRD-negative patients.

Patients randomized to consolidation received 1,000 mg of obinutuzumab weekly for the first four doses, and then every other week for four additional doses.

Obinutuzumab was well tolerated with minimal infusion-related reactions and toxicity, Dr. Munir said.

Despite the low recruitment, both the phase 2 and 3 endpoints were assessed as positive, because the consolidation strategy was so efficacious, Dr. Munir noted, concluding that the findings provide further evidence of the value of MRD negativity for improving outcomes in CLL.

The GALACTIC trial was developed by the GALACTIC Trial Management Group with the support of the UKCLL/NCRI CLL Clinical Trials Subgroup. The trial is funded by Cancer Research UK and Roche and sponsored by the University of Leeds. Dr. Munir reported having no disclosures.

[email protected]

EDINBURGH – Consolidation therapy with obinutuzumab after chemoimmunotherapy for B-cell chronic lymphocytic leukemia (B-CLL) was highly effective for eradicating minimal residual disease (MRD) within 6 months following randomization in the seamless phase 2/3 GALACTIC trial.

Of 14 patients who were MRD positive after chemoimmunotherapy and randomized to consolidation with the type II monoclonal antibody targeting the CD20 antigen, 10 achieved MRD negativity in the bone marrow by 6 months, and 13 achieved MRD negativity in the peripheral blood by 6 months, Talha Munir, MD, reported at the International Workshop on Chronic Lymphocytic Leukemia.

“And that translated into [progression-free survival] improvement in the consolidation arm,” said Dr. Munir of St. James’s University, Leeds, England.

The median progression-free survival in that arm was not reached, whereas progression-free survival in 15 MRD-positive patients randomized to the nonconsolidation arm was 16.6 months, he said.

Further, no difference was seen in median progression-free survival, overall survival, or MRD duration between the consolidation arm and 19 patients who were not randomized because of MRD negativity after chemoimmunotherapy, he noted.

Achieving MRD negativity in CLL confers a survival advantage, and obinutuzumab has shown greater efficacy with respect to MRD in CLL when compared with previous anti-CD20 antibodies, and it is less immune suppressive than the anti-CD52 antibody alemtuzumab, he explained.

The GALACTIC trial was designed to assess the safety and efficacy of obinutuzumab consolidation for eradicating MRD and whether its effects would prolong progression-free survival in patients with B-CLL who recently responded to chemoimmunotherapy. Those achieving complete response or partial response at 3-24 months after chemoimmunotherapy, and who remained MRD-positive, were eligible for randomization.

The planned sample size was 188 patients, but the trial was closed early in February 2017 because of poor recruitment; a total of 48 patients were enrolled, including the 19 nonrandomized, MRD-negative patients.

Patients randomized to consolidation received 1,000 mg of obinutuzumab weekly for the first four doses, and then every other week for four additional doses.

Obinutuzumab was well tolerated with minimal infusion-related reactions and toxicity, Dr. Munir said.

Despite the low recruitment, both the phase 2 and 3 endpoints were assessed as positive, because the consolidation strategy was so efficacious, Dr. Munir noted, concluding that the findings provide further evidence of the value of MRD negativity for improving outcomes in CLL.

The GALACTIC trial was developed by the GALACTIC Trial Management Group with the support of the UKCLL/NCRI CLL Clinical Trials Subgroup. The trial is funded by Cancer Research UK and Roche and sponsored by the University of Leeds. Dr. Munir reported having no disclosures.

[email protected]

EDINBURGH – Consolidation therapy with obinutuzumab after chemoimmunotherapy for B-cell chronic lymphocytic leukemia (B-CLL) was highly effective for eradicating minimal residual disease (MRD) within 6 months following randomization in the seamless phase 2/3 GALACTIC trial.

Of 14 patients who were MRD positive after chemoimmunotherapy and randomized to consolidation with the type II monoclonal antibody targeting the CD20 antigen, 10 achieved MRD negativity in the bone marrow by 6 months, and 13 achieved MRD negativity in the peripheral blood by 6 months, Talha Munir, MD, reported at the International Workshop on Chronic Lymphocytic Leukemia.

“And that translated into [progression-free survival] improvement in the consolidation arm,” said Dr. Munir of St. James’s University, Leeds, England.

The median progression-free survival in that arm was not reached, whereas progression-free survival in 15 MRD-positive patients randomized to the nonconsolidation arm was 16.6 months, he said.

Further, no difference was seen in median progression-free survival, overall survival, or MRD duration between the consolidation arm and 19 patients who were not randomized because of MRD negativity after chemoimmunotherapy, he noted.

Achieving MRD negativity in CLL confers a survival advantage, and obinutuzumab has shown greater efficacy with respect to MRD in CLL when compared with previous anti-CD20 antibodies, and it is less immune suppressive than the anti-CD52 antibody alemtuzumab, he explained.

The GALACTIC trial was designed to assess the safety and efficacy of obinutuzumab consolidation for eradicating MRD and whether its effects would prolong progression-free survival in patients with B-CLL who recently responded to chemoimmunotherapy. Those achieving complete response or partial response at 3-24 months after chemoimmunotherapy, and who remained MRD-positive, were eligible for randomization.

The planned sample size was 188 patients, but the trial was closed early in February 2017 because of poor recruitment; a total of 48 patients were enrolled, including the 19 nonrandomized, MRD-negative patients.

Patients randomized to consolidation received 1,000 mg of obinutuzumab weekly for the first four doses, and then every other week for four additional doses.

Obinutuzumab was well tolerated with minimal infusion-related reactions and toxicity, Dr. Munir said.

Despite the low recruitment, both the phase 2 and 3 endpoints were assessed as positive, because the consolidation strategy was so efficacious, Dr. Munir noted, concluding that the findings provide further evidence of the value of MRD negativity for improving outcomes in CLL.

The GALACTIC trial was developed by the GALACTIC Trial Management Group with the support of the UKCLL/NCRI CLL Clinical Trials Subgroup. The trial is funded by Cancer Research UK and Roche and sponsored by the University of Leeds. Dr. Munir reported having no disclosures.

[email protected]

Germline DDX41 mutations were found to be relatively prevalent and showed favorable outcomes in a cohort of patients with myelodysplastic syndromes or acute myeloid leukemia, according to a genetic analysis.

Jezperklauzen/ThinkStock

The results demonstrate that systematic genetic testing for DDX41 mutations may aid in clinical decision making for adults with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML).

“We screened a large, unselected cohort of adult patients diagnosed with MDS/AML to analyze the biological and clinical features of DDX41-related myeloid malignancies,” wrote Marie Sébert, MD, PhD, of Hôpital Saint Louis in Paris and colleagues. The results were published in Blood.

The researchers used next-generation sequencing to analyze blood and bone marrow samples from 1,385 patients with MDS or AML to detect DDX41 mutations. A variant allele frequency of greater than 0.4 was regarded as indicative of a germline origin, and only specific variants (minor allele frequency of less than 0.01) were included.

The team analyzed various parameters relevant to DDX41-related myeloid disorders, including patient demographics, karyotyping, and treatment response rates, in addition to the prevalence of DDX41-related malignancies.

A total of 28 distinct germline DDX41 variants were detected among 43 unrelated patients. The researchers classified 21 of the variants as causal, with the rest being of unknown significance.

“We focused on the 33 patients having causal variants, representing 2.4% of our cohort,” they wrote.

The majority of patients with DDX41-related MDS/AML were male, with a median age of 69 years. Few patients (27%) had a family history of blood malignancies, while the majority of patients (85%) had a normal karyotype.

With respect to treatment, most high-risk patients received either azacitidine or intensive chemotherapy, with overall response rates of 73% and 100%, respectively. The median overall survival was 5.2 years.

There are currently no consensus recommendations on genetic counseling and follow-up of asymptomatic carriers and more studies are needed to refine clinical management and genetic counseling, the researchers wrote. “However, in our experience, DDX41-mutated patients frequently presented mild cytopenias years before overt hematological myeloid malignancy, suggesting that watchful surveillance would allow the detection of disease evolution.”

No funding sources were reported, and the authors reported having no conflicts of interest.

SOURCE: Sébert M et al. Blood. 2019 Sep 4. doi: 10.1182/blood.2019000909.

Germline DDX41 mutations were found to be relatively prevalent and showed favorable outcomes in a cohort of patients with myelodysplastic syndromes or acute myeloid leukemia, according to a genetic analysis.

Jezperklauzen/ThinkStock

The results demonstrate that systematic genetic testing for DDX41 mutations may aid in clinical decision making for adults with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML).

“We screened a large, unselected cohort of adult patients diagnosed with MDS/AML to analyze the biological and clinical features of DDX41-related myeloid malignancies,” wrote Marie Sébert, MD, PhD, of Hôpital Saint Louis in Paris and colleagues. The results were published in Blood.

The researchers used next-generation sequencing to analyze blood and bone marrow samples from 1,385 patients with MDS or AML to detect DDX41 mutations. A variant allele frequency of greater than 0.4 was regarded as indicative of a germline origin, and only specific variants (minor allele frequency of less than 0.01) were included.

The team analyzed various parameters relevant to DDX41-related myeloid disorders, including patient demographics, karyotyping, and treatment response rates, in addition to the prevalence of DDX41-related malignancies.

A total of 28 distinct germline DDX41 variants were detected among 43 unrelated patients. The researchers classified 21 of the variants as causal, with the rest being of unknown significance.

“We focused on the 33 patients having causal variants, representing 2.4% of our cohort,” they wrote.

The majority of patients with DDX41-related MDS/AML were male, with a median age of 69 years. Few patients (27%) had a family history of blood malignancies, while the majority of patients (85%) had a normal karyotype.

With respect to treatment, most high-risk patients received either azacitidine or intensive chemotherapy, with overall response rates of 73% and 100%, respectively. The median overall survival was 5.2 years.

There are currently no consensus recommendations on genetic counseling and follow-up of asymptomatic carriers and more studies are needed to refine clinical management and genetic counseling, the researchers wrote. “However, in our experience, DDX41-mutated patients frequently presented mild cytopenias years before overt hematological myeloid malignancy, suggesting that watchful surveillance would allow the detection of disease evolution.”

No funding sources were reported, and the authors reported having no conflicts of interest.

SOURCE: Sébert M et al. Blood. 2019 Sep 4. doi: 10.1182/blood.2019000909.

Germline DDX41 mutations were found to be relatively prevalent and showed favorable outcomes in a cohort of patients with myelodysplastic syndromes or acute myeloid leukemia, according to a genetic analysis.

Jezperklauzen/ThinkStock

The results demonstrate that systematic genetic testing for DDX41 mutations may aid in clinical decision making for adults with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML).

“We screened a large, unselected cohort of adult patients diagnosed with MDS/AML to analyze the biological and clinical features of DDX41-related myeloid malignancies,” wrote Marie Sébert, MD, PhD, of Hôpital Saint Louis in Paris and colleagues. The results were published in Blood.

The researchers used next-generation sequencing to analyze blood and bone marrow samples from 1,385 patients with MDS or AML to detect DDX41 mutations. A variant allele frequency of greater than 0.4 was regarded as indicative of a germline origin, and only specific variants (minor allele frequency of less than 0.01) were included.

The team analyzed various parameters relevant to DDX41-related myeloid disorders, including patient demographics, karyotyping, and treatment response rates, in addition to the prevalence of DDX41-related malignancies.

A total of 28 distinct germline DDX41 variants were detected among 43 unrelated patients. The researchers classified 21 of the variants as causal, with the rest being of unknown significance.

“We focused on the 33 patients having causal variants, representing 2.4% of our cohort,” they wrote.

The majority of patients with DDX41-related MDS/AML were male, with a median age of 69 years. Few patients (27%) had a family history of blood malignancies, while the majority of patients (85%) had a normal karyotype.

With respect to treatment, most high-risk patients received either azacitidine or intensive chemotherapy, with overall response rates of 73% and 100%, respectively. The median overall survival was 5.2 years.

There are currently no consensus recommendations on genetic counseling and follow-up of asymptomatic carriers and more studies are needed to refine clinical management and genetic counseling, the researchers wrote. “However, in our experience, DDX41-mutated patients frequently presented mild cytopenias years before overt hematological myeloid malignancy, suggesting that watchful surveillance would allow the detection of disease evolution.”

No funding sources were reported, and the authors reported having no conflicts of interest.

SOURCE: Sébert M et al. Blood. 2019 Sep 4. doi: 10.1182/blood.2019000909.

Gene editing of donor stem cells prior to transplantation into a patient with both HIV infection and acute lymphoblastic leukemia (ALL) was safe and effectively treated the patient’s leukemia, but failed to resolve his HIV, investigators reported.

NIAID

The 27-year-old man received an HLA-matched transplant of hematopoietic stem and progenitor cells (HSPCs) that had been genetically engineered to lack CCR5, a key gateway for HIV entry into cells.

Although the transplant resulted in complete remission of leukemia with full donor chimerism, only about 9% of the posttransplant lymphocytes showed disruption of CCR5, and during a brief trial of antiretroviral therapy interruption his HIV viral load rebounded, reported Hongkui Deng, PhD, and colleagues from Peking University in China.

Although the experiment did not meet its goal of a drug-free HIV remission, it serves as a proof of concept for the use of CRISPR-Cas9 (clustered regularly interspaced palindromic repeats/CRISPR-associated protein 9) gene editing to treat HIV infection, the authors contend.

“These results show the proof of principle that transplantation and long-term engraftment of CRISPR-edited allogeneic HSPCs can be achieved; however, the efficiency of the response was not adequate to achieve the target of cure of HIV-1 infection,” they wrote in a brief report published in the New England Journal of Medicine.

As previously reported, other research groups have investigated genetic editing to mimic a naturally occurring mutation that effectively disables the CCR5 HIV coreceptor, preventing the retrovirus from entering healthy cells. The mutation was first identified in a man named Timothy Brown who came to be known as “the Berlin patient” after he was apparently cured of HIV infection after a bone marrow transplant from a donor who had the mutation.

Dr. Deng and colleagues took advantage of HSPC transplantation, a standard therapy for ALL to see whether it could also have beneficial effects on concomitant HIV infection.

They treated donor HSPCs with CRISPR-Cas9 to ablate CCR5 and then delivered them to the patient along with additional CD34-depleted donor cells from mobilized peripheral blood.

The transplant was a success, with neutrophil engraftment on day 13 and platelet engraftment on day 27, and the leukemia was in morphologic complete remission at week 4 following transplantation. The patient remained in complete remission from leukemia throughout the 19-month follow-up period, with full donor chimerism .

However, when a planned interruption of antiretroviral therapy was carried out at 7 months post transplant, the serum viral load increased to 3 × 10⁷ copies/ml at week 4 following interruption, and the patient was restarted on the drug. His viral levels gradually decreased to undetectable level during the subsequent months.

The investigators noted that 2 weeks after the drug interruption trial was started there was a small increase in the percentage of CCR5 insertion/deletions.

“The low efficiency of gene editing in the patient may be due to the competitive engraftment of the coinfused HSPCs in CD34-depleted cells and the persistence of donor T cells. To further clarify the anti-HIV effect of CCR5-ablated HSPCs, it will be essential to increase the gene-editing efficiency of our CRISPR-Cas9 system and improve the transplantation protocol,” they wrote.

The study was funded by the Beijing Municipal Science and Technology Commission and others (unspecified). All authors reported having nothing to disclose.

SOURCE: Xu L et al. N Engl J Med. 2019. doi: 10.1056/NEJMoa1817426.

Gene editing of donor stem cells prior to transplantation into a patient with both HIV infection and acute lymphoblastic leukemia (ALL) was safe and effectively treated the patient’s leukemia, but failed to resolve his HIV, investigators reported.

NIAID

The 27-year-old man received an HLA-matched transplant of hematopoietic stem and progenitor cells (HSPCs) that had been genetically engineered to lack CCR5, a key gateway for HIV entry into cells.

Although the transplant resulted in complete remission of leukemia with full donor chimerism, only about 9% of the posttransplant lymphocytes showed disruption of CCR5, and during a brief trial of antiretroviral therapy interruption his HIV viral load rebounded, reported Hongkui Deng, PhD, and colleagues from Peking University in China.

Although the experiment did not meet its goal of a drug-free HIV remission, it serves as a proof of concept for the use of CRISPR-Cas9 (clustered regularly interspaced palindromic repeats/CRISPR-associated protein 9) gene editing to treat HIV infection, the authors contend.

“These results show the proof of principle that transplantation and long-term engraftment of CRISPR-edited allogeneic HSPCs can be achieved; however, the efficiency of the response was not adequate to achieve the target of cure of HIV-1 infection,” they wrote in a brief report published in the New England Journal of Medicine.

As previously reported, other research groups have investigated genetic editing to mimic a naturally occurring mutation that effectively disables the CCR5 HIV coreceptor, preventing the retrovirus from entering healthy cells. The mutation was first identified in a man named Timothy Brown who came to be known as “the Berlin patient” after he was apparently cured of HIV infection after a bone marrow transplant from a donor who had the mutation.

Dr. Deng and colleagues took advantage of HSPC transplantation, a standard therapy for ALL to see whether it could also have beneficial effects on concomitant HIV infection.

They treated donor HSPCs with CRISPR-Cas9 to ablate CCR5 and then delivered them to the patient along with additional CD34-depleted donor cells from mobilized peripheral blood.

The transplant was a success, with neutrophil engraftment on day 13 and platelet engraftment on day 27, and the leukemia was in morphologic complete remission at week 4 following transplantation. The patient remained in complete remission from leukemia throughout the 19-month follow-up period, with full donor chimerism .

However, when a planned interruption of antiretroviral therapy was carried out at 7 months post transplant, the serum viral load increased to 3 × 10⁷ copies/ml at week 4 following interruption, and the patient was restarted on the drug. His viral levels gradually decreased to undetectable level during the subsequent months.

The investigators noted that 2 weeks after the drug interruption trial was started there was a small increase in the percentage of CCR5 insertion/deletions.

“The low efficiency of gene editing in the patient may be due to the competitive engraftment of the coinfused HSPCs in CD34-depleted cells and the persistence of donor T cells. To further clarify the anti-HIV effect of CCR5-ablated HSPCs, it will be essential to increase the gene-editing efficiency of our CRISPR-Cas9 system and improve the transplantation protocol,” they wrote.

The study was funded by the Beijing Municipal Science and Technology Commission and others (unspecified). All authors reported having nothing to disclose.

SOURCE: Xu L et al. N Engl J Med. 2019. doi: 10.1056/NEJMoa1817426.

Gene editing of donor stem cells prior to transplantation into a patient with both HIV infection and acute lymphoblastic leukemia (ALL) was safe and effectively treated the patient’s leukemia, but failed to resolve his HIV, investigators reported.

NIAID

The 27-year-old man received an HLA-matched transplant of hematopoietic stem and progenitor cells (HSPCs) that had been genetically engineered to lack CCR5, a key gateway for HIV entry into cells.

Although the transplant resulted in complete remission of leukemia with full donor chimerism, only about 9% of the posttransplant lymphocytes showed disruption of CCR5, and during a brief trial of antiretroviral therapy interruption his HIV viral load rebounded, reported Hongkui Deng, PhD, and colleagues from Peking University in China.

Although the experiment did not meet its goal of a drug-free HIV remission, it serves as a proof of concept for the use of CRISPR-Cas9 (clustered regularly interspaced palindromic repeats/CRISPR-associated protein 9) gene editing to treat HIV infection, the authors contend.

“These results show the proof of principle that transplantation and long-term engraftment of CRISPR-edited allogeneic HSPCs can be achieved; however, the efficiency of the response was not adequate to achieve the target of cure of HIV-1 infection,” they wrote in a brief report published in the New England Journal of Medicine.

As previously reported, other research groups have investigated genetic editing to mimic a naturally occurring mutation that effectively disables the CCR5 HIV coreceptor, preventing the retrovirus from entering healthy cells. The mutation was first identified in a man named Timothy Brown who came to be known as “the Berlin patient” after he was apparently cured of HIV infection after a bone marrow transplant from a donor who had the mutation.

Dr. Deng and colleagues took advantage of HSPC transplantation, a standard therapy for ALL to see whether it could also have beneficial effects on concomitant HIV infection.

They treated donor HSPCs with CRISPR-Cas9 to ablate CCR5 and then delivered them to the patient along with additional CD34-depleted donor cells from mobilized peripheral blood.

The transplant was a success, with neutrophil engraftment on day 13 and platelet engraftment on day 27, and the leukemia was in morphologic complete remission at week 4 following transplantation. The patient remained in complete remission from leukemia throughout the 19-month follow-up period, with full donor chimerism .

However, when a planned interruption of antiretroviral therapy was carried out at 7 months post transplant, the serum viral load increased to 3 × 10⁷ copies/ml at week 4 following interruption, and the patient was restarted on the drug. His viral levels gradually decreased to undetectable level during the subsequent months.

The investigators noted that 2 weeks after the drug interruption trial was started there was a small increase in the percentage of CCR5 insertion/deletions.

“The low efficiency of gene editing in the patient may be due to the competitive engraftment of the coinfused HSPCs in CD34-depleted cells and the persistence of donor T cells. To further clarify the anti-HIV effect of CCR5-ablated HSPCs, it will be essential to increase the gene-editing efficiency of our CRISPR-Cas9 system and improve the transplantation protocol,” they wrote.

The study was funded by the Beijing Municipal Science and Technology Commission and others (unspecified). All authors reported having nothing to disclose.

SOURCE: Xu L et al. N Engl J Med. 2019. doi: 10.1056/NEJMoa1817426.