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Transplantation and Cellular Therapy Meetings

Robert Korngold, PhD, chief of The Division of Research at John Theurer Cancer Center, reflects on the progress made in the field of bone marrow transplant. Most strikingly, new approaches have opened the opportunity of a bone marrow transplant to virtually all eligible patients, he noted.

Bone marrow transplants have become the platform from which immunotherapy and vaccines can be built, Korngold believes. New methods and approaches are becoming available, which lend strength to the graph versus tumor response in the hope of avoiding relapses and complications.

View more from the 2017 BMT Tandem Meetings

Robert Korngold, PhD, John Theurer Cancer Center looks back on the advances we've made so far in bone marrow transplant.

Robert Korngold on Advances in Bone Marrow Transplant

Treatment with an inactivated varicella zoster virus vaccine, known as V212, lowered the cumulative incidence rate of herpes zoster (HZ) infection and HZ-related complications for patients undergoing autologous stem cell transplantation (ASCT), according to findings from a phase III study presented at the 2017 BMT Tandem Meetings.

After 2.3 years of follow-up, confirmed cases of HZ by PCR were seen in 42 of 538 patients (7.8%) treated with the vaccine versus 113 of 535 patients (21.1%) who received a placebo (

 <.0001). Once adjusting for age and antiviral prophylaxis, the vaccine was estimated to be 63.8% effective against HZ (95% CI, 48.4-74.6).

"The study demonstrates that the inactivated varicella vaccine is very effective for prevention of herpes zoster after autologous transplant," summarized Drew J. Winston, MD, from the University of California Los Angeles Medical Center, during his talk at the meeting. "The vaccine also reduces the incidence of moderate-to-severe pain, post-herpetic neuralgia, and herpes zoster complications after autologous transplantation."

In the trial, patients received V212 (n = 560) and a matching placebo (n = 564) at 0.5 mL subcutaneously approximately 30 days prior to ASCT (range, 5-60), followed by 3 subsequent injections on days 30, 60, and 90 post-transplant. An additional arm looked at a high antigen version of the vaccine (n = 106). The high antigen arm was not included in the efficacy analysis but was part of the safety assessment.

Patient characteristics were well-balanced between the groups. In the investigational arm, the most common underlying diseases were non-Hodgkin's lymphoma (42%), multiple myeloma (44%), and Hodgkin's lymphoma (10%). Ninety percent of patients received conditioning chemotherapy.

Post-transplant maintenance therapy was received by a third of patients, most commonly lenalidomide (15%), bortezomib (11%), and rituximab (7%). Post-treatment antiviral therapy was utilized for ≤3 months for a third of patients, with 20% receiving these therapies for 3 to 6 months and 37% for >6 months. Twelve percent of patients did not receive antiviral therapy.

The primary endpoint was the incidence of HZ, which was deemed statistically improved if the lower end of the confidence interval was greater than 25%. Secondary endpoints focused on severity of HZ-associated pain, HZ complications, and the incidence of post-herpetic neuralgia (PHN). Only those who went on to receive ASCT and the vaccine were include in the efficacy analysis.

Moderate-to-severe HZ-related pain was experienced by 3.5% of those in the vaccine arm versus 11.4% in the placebo group, showing the vaccine was 69.5% effective for this endpoint (95% CI, 0.490-0.818). PHN occurred in just 0.5% of those in the vaccine arm versus 3.4% in the placebo group (83.7% efficacy; 95% CI, 0.446-0.952). HZ complications occurred in 2.2% versus 8.2% of those in the vaccine and placebo arms, respectively (73.5% efficacy; 95% CI, 0.498-0.860).

In those aged <50 years, in the vaccine arm (n = 154) the HZ incidence was 4.5% compared with 17.9% in the placebo arm (n = 151). In those ≥50 years of age, in the vaccine group (n = 384) the HZ rate was 9.1% versus 22.4% in the placebo arm (n = 384).

In those who received antivirals for ≤3 months, in the vaccine arm (n = 228) 9.7% had an HZ infection versus 21.3% in the placebo group (n = 239). In those treated with antivirals for 3 to 6 months, the HZ rate was 7.1% in the vaccine group (n = 310) versus 20.9% in the placebo group (n = 296).

Vaccine-related adverse events (AEs) occurred in 32.6% of patients in the investigational arm versus 12.6% in the placebo group, many of these events were associated with the high antigen vaccine. Most of the events reported were injection site reactions (29.1% vs 6.5%). The rates of serious AEs were similar between the vaccine and placebo arms, at 32.9% and 32.7%, respectively. Serious vaccine-related AEs were 0.8% and 0.9%, in the V212 and placebo arms, respectively.

A larger phase III study is examining the efficacy, safety, and tolerability of V212 for patients with solid tumors or hematologic malignancy. The trial is comparing the vaccine with placebo across 5307 patients, with primary endpoints of reduction in HZ cases and safety. The study is fully enrolled with an estimated completion date in April 2017 (NCT01254630).

Winston DJ, Mullane KM, Boeckh MJ, et al. A Phase III, Double-Blind, Randomized, Placebo-Controlled, Multicenter Clinical Trial to Study the Safety, Tolerability, Efficacy, and Immunogenicity of Inactivated Vzv Vaccine (ZVIN) in Recipients of Autologous Hematopoietic Cell Transplants (Auto-HCTs). Presented at: BMT Tandem Meetings; February 22-26, 2017; Orlando, FL. Abstract 6.

“These results indicate that V212 might offer a way to help reduce the risk of HZ and HZ-related complications in this vulnerable, immunocompromised patient population,” Eliav Barr, MD, senior vice president, Merck Research Laboratories, the company developing the vaccine, said in a statement. “We look forward to exploring these data further and to reviewing the results of an additional phase III study that is underway in immunocompromised patients with malignancies.”

Treatment with an inactivated varicella zoster virus vaccine, known as V212, lowered the cumulative incidence rate of herpes zoster infection and complications for patients undergoing autologous hematopoietic stem cell transplantation.

Vaccine Limits Herpes Zoster Infections Following Stem Cell Transplant

Rates of early relapse post-autologous stem cell transplant (ASCT) in patients with relapsing multiple myeloma have not changed over time, but post-relapse survival among early relapsers has improved for patients transplanted after 2005 and for those relapsing since 2008.

In an analysis of patients enrolled in the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, the proportion of patients relapsing within 2 years has remained stable at slightly more than one-third over 3 time periods (2001-2004, 2005-2008, and 2009-2013), reported Angela Dispenzieri, MD, at the 2017 BMT Tandem Meetings.

Patients transplanted in the latter 2 periods had significantly better post-relapse survival at 1 year, 2 years, 3 years, and 5 years compared with those transplanted from 2001 to 2004 (

Patients who relapsed at 2008 or later had a 72% 1-year post-relapse survival compared with 61% for those who relapsed before 2008. Two-, 3-, and 5-year post-relapse survival was 55%, 43%, and 26% in patients who relapsed at 2008 or after, compared with 45%, 33%, and 21% among those who relapsed before 2008 (

“These data seem to suggest that it was not so much when you were transplanted but really when you relapsed…if you were one of those patients who relapsed early,” said Dispenzieri, from the Bone Marrow Transplant Program at Mayo Clinic, Rochester, Minnesota.

Included in the analysis were patients from the CIBMTR registry who received a single ASCT between January 2001 and December 2013. Eligible patients had to have ASCT within 12 months of diagnosis and were required to have >100 days of post-transplant follow-up. For the purpose of analyzing relapse-free survival, patients had to have at least 4 years of post-ASCT follow-up.

Patients diagnosed during each period had a similar median age at transplant, similar Karnofsky scores, and similar renal function. During the most recent period, the proportion of patients with advanced MM was lower (30%) compared with 2005 to 2008 (38%) and 2001 to 2004 (43%).

“What really was different was how patients were managed,” Dispenzieri said. Induction during the earliest period was mostly with “VAD [vincristine, Adriamycin, and dexamethasone] types of regimens and very little in terms of novel therapies” whereas during the most recent period, almost 70% of patients received lenalidomide, bortezomib, and dexamethasone or another triplet as induction. The maintenance strategy was overwhelmingly no maintenance during 2001 to 2004, whereas during 2009 to 2013, the vast majority received maintenance therapy with novel agents and only a small fraction did not receive maintenance.

Patients in the most recent period were more likely to receive 200 mg/m

 of melphalan as a conditioning regimen compared with 2005 to 2008 and 2001 to 2004 (90% vs 84% vs 81%, respectively). The rate of complete responses did not change substantially over the 3 time periods. “Patients [in the most recent period] tended to be more sensitive to chemotherapy, probably because they were getting more active regimens, and a higher percentage were transplanted within 6 months of diagnosis in the most recent period [42% vs 28% vs 32%],” Dispenzieri said.

Overall survival post-ASCT was significantly superior by about 15% during the most recent period compared with the earliest period (

The early relapse rates (within 2 years) were 38%, 38%, and 35% over the 3 time periods. The only characteristic that appeared to predict early relapse was advanced disease stage. On multivariate analysis, predictors of early relapse were resistance to chemotherapy (

 = .0071), International Staging System (ISS)/Durie-Salmon (DS) stage III disease at diagnosis (

 = .0037), and receipt of transplant from 2001 to 2008 (

Use of a novel agent for post-ASCT maintenance was protective against relapse (

 = .0180). There was a strong interaction between year of ASCT and type of post-ASCT maintenance on early relapse. During the 2001 the 2008 period, the hazard ratio (HR) for early relapse was 1.219 (

 <.0001) compared with no maintenance or use of non-novel agents as maintenance compared with the use of novel agents. During the 2009 to 2013 period, the HR for no/other maintenance was 1.256 (

 <.0001) compared with use of novel agents.

Patients who relapsed early had a 5-year overall survival rate from transplant of 32%, compared with 80% among those patients who did not have early relapse.

Among the early relapsers, post-relapse survival was significantly superior in the 2 most recent time periods compared with 2001 to 2004 (

 = .006). One-year post-relapse survival was 58%, 70%, and 68% in the groups receiving ASCT during 2001 to 2004, 2005 to 2008, and 2009 to 2013, respectively. At 3 years, the post-relapse survival rates were 32%, 42%, and 41%, respectively, and at 5 years, 22%, 25%, and 23%, respectively.

In assessing post-relapse survival by when patients relapsed, patients who relapsed in the more modern era (2008 or after) had significantly superior post-relapse survival (

 <.01). Comparing patients who relapsed before 2008 to those who relapsed at 2008 or later, the 1-, 2-, 3-, and 5-year post-relapse survival rates in these 2 groups were 61% and 72%, 45% and 55%, 33% and 43%, and 21% and 26%.

Multivariate analysis showed that predictors of worse post-relapse survival were early relapse (

 = .0002), ISS/DS stage III at diagnosis (

 <.0001), receipt of 2 or more lines of chemotherapy (

 = .0028). Receipt of a novel agent for maintenance predicted better post-relapse survival (

Dispenzieri A, Kumar S, Zhang M-J, et al Trends in survival outcomes among patients relapsing early after autologous stem cell transplantation for multiple myeloma (CIBMTR Study # MM14-03). Presented at: BMT Tandem Meetings; February 23-26, 2017; Orlando, Florida. Abstract 63.

Rates of early relapse post-autologous stem cell transplant in patients with relapsing multiple myeloma have not changed over time, but post-relapse survival among early relapsers has improved for patients transplanted after 2005 and for those relapsing since 2008.
 

Outcomes Have Improved Over Time in Myeloma Patients Relapsing Early After ASCT

Jeffrey Lancet, MD, of Moffitt Cancer Center, explains the use of CPX-351 compared with induction chemotherapy for older adult patients with acute myeloid leukemia (AML).

More patients with AML were able to proceed to transplant following treatment with CPX-351 compared with the traditional 7+3 chemotherapy regimen, Lancet notes. As such, Lancet believes that CPX-351 could serve as a potential bridge to successful allogeneic transplant.

Data from the phase III study showed that 65% of patients in the CPX-351 arm who proceeded to transplant survived, at a follow-up of 521 days. In the standard of care arm, 33% of patients survived at a 442-day follow-up. 

Dr. Lancet of Moffitt Cancer Center explains the use of CPX-351 treatment compared to induction chemotherapy, for older adult patients with acute myeloid leukemia.

Dr. Lancet on CPX-351 Compared to Chemotherapy for Older Adults With AML

Partow Kebriaei, MD, of MD Anderson Cancer Center, discusses the SIERRA clinical trial, in which patients over the age of 55 with acute myeloid leukemia (AML) are receiving treatment with a radiolabeled anti-CD45 antibody known as Iomab-B or conventional therapy as a preconditioning regimen before allogeneic hematopoietic cell transplantation.

The targeted administration of radiation helps to treat older patients with AML, as it is a less intense therapy, notes Kabriaei. This reduced intensity is especially important for older patients, who tend to have less tolerance for toxicities. Iomab-B offers a novel therapy for this population of patients, she adds. 

Partow Kebriaei, MD, discusses the Iomab-B clinical trial for older patients with acute myeloid leukemia.

Dr. Kebriaei on the Iomab-B Clinical Trial

Carfilzomib can be safely combined with melphalan, 200 mg/m

, in a conditioning regimen prior to autologous hematopoietic cell transplantation (HCT) in patients with relapsed multiple myeloma (MM), and single-agent carfilzomib shows promise for post-transplant maintenance therapy in responders to transplant, according to data from a phase I/II clinical trial.

Of the 48 patients who received carfilzomib plus melphalan as a conditioning regimen, the median time for engraftment was 10 days for neutrophils and 15 days for platelets, and there were no dose-limiting toxicities or non-hematologic grade 4 toxicities.

Of the 27 patients who did not have disease progression by 100 days post-transplant, and were started on maintenance therapy with single-agent carfilzomib (given as either 3 or 4 doses over 28 days), 31% had an improvement in response category during maintenance. The interim 12-month progression-free survival on maintenance was 67.5%, said Luciano Costa, MD, PhD, at the 2017 BMT Tandem Meetings in Orlando.

“Carfilzomib as single agent can be safely used as maintenance following carfilzomib/melphalan, and can sustain remission in most of the patients in this high-risk population,” Costa said.

Synergism between proteasome inhibitors and alkylators outside the transplant setting has been demonstrated preclinically and clinically. Autologous HCT in the relapsed setting, including in a second transplant, is usually followed by shorter remissions than in the upfront setting, highlighting the need for post-transplant therapy, said Costa, associate professor of medicine, blood and marrow transplantation and cell therapy program at the University of Alabama, Birmingham. Although post-autologous HCT maintenance therapy with thalidomide, lenalidomide, or bortezomib is well-established in the frontline setting, data on the use of post-autologous HCT maintenance therapy in the relapsed setting are limited.

Carfilzomib used at the conventional schedule is cumbersome; it is typically administered on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. The dose and schedule for carfilzomib as maintenance has not been determined.

The data presented here were from a 2-phase investigation: a phase I dose-escalation study to determine the maximum tolerated dose of carfilzomib when added to melphalan conditioning for autologous HCT in relapsed MM, and phase II sought to evaluate the anti-myeloma activity and toxicity of the preparative regimen and to determine the safety and patient preference of 2 schedules of carfilzomib maintenance therapy.

Eligible patients had relapsed MM, including those who received a prior autologous HCT. They were required to have at least a minimal response to the most recent line of therapy, including carfilzomib. To be eligible for maintenance, patients could not have had disease progression by 100 days post-transplant. The 2 maintenance carfilzomib schedules were 36 mg/m

 on days 1, 8, and 15 (schedule A), or alternatively on days 1, 2, 15, and 16 (schedule B) for 12 four-week cycles. Patients on maintenance received 2 cycles on each schedule, and then had their choice of schedules for the remainder of maintenance.

Dose-limiting toxicity in phase I was defined as delayed engraftment (>30 days) or any grade 4 non-hematologic toxicities, selected grade- 3 toxicity, or any reaction to the first dose of carfilzomib that precluded a second dose.

The 48 patients enrolled received a median of 3 prior lines of therapy. Nearly all patients received prior bortezomib and lenalidomide and about two-thirds had received prior autologous HCT. “As the trial evolved, it became more common that patients had received prior carfilzomib: 63% of patients in the phase 2,” he said. Two of the 48 patients were determined not to be eligible for conditioning and were included only in the toxicity analysis.

There was no dose-limiting toxicity in the phase I or phase II cohort, and therefore the maximum tolerated dose was not reached. The trial proceeded to phase II with the expansion of the last dose of carfilzomib, which was 27 mg/m

 on day 3 prior to melphalan followed by 56 mg/m

 on day 2 prior to melphalan. The main grade 3/4 non-hematologic toxicity during conditioning was infection (38%). Median time to engraftment was 10 days for neutrophils and 15 days for platelets. Two patients had disease progression from pre-transplant to post-transplant. Of the remaining 44 patients, the proportion with very good partial response (VGPR) or better improved from 13.7% pre-conditioning to 59.2% at 100 days post-transplant.

Of the 30 patients eligible for maintenance, 2 had disease progression before day 100 post-transplant and 1 withdrew consent, leaving 27 patients that started maintenance. Nine of these are currently on therapy, and 10 have completed maintenance. Two discontinued due to toxicity (1 with grade 3 congestive heart failure, and 1 with grade 4 acute kidney injury).

Most patients were comfortable with either maintenance schedule. “My impression is that local people prefer weekly because they’re in and out, but for people who have to travel, they prefer every other week…to have fewer trips.”

Of the 29 patients who were eligible for and consented to maintenance, the proportion with VGPR or better improved to 75.8%. “Keep in mind that the study is ongoing, and some of those patients might not have yet reached their best response,” said Costa.

Costa LJ, Landau H, Chhabra S, et al. A phase 1/2 trial of carfilzomib + high-dose melphalan conditioning for auto-HCT followed by carfilzomib maintenance for patients with relapsed multiple myeloma. Presented at: BMT Tandem Meetings; February 23-26, 2017; Orlando, Florida.

According to data from a phase I/II clinical trial, carfilzomib can be safely combined with melphalan in a conditioning regimen prior to autologous hematopoietic cell transplantation in patients with relapsed multiple myeloma.

Carfilzomib Maintenance Improves Response Following Transplant in Relapsed Multiple Myeloma

More patients with acute myeloid leukemia (AML) could proceed to transplant following treatment with CPX-351 (Vyxeos) compared with the traditional 7+3 chemotherapy regimen, according to an exploratory analysis presented at the 2017 BMT Tandem Meetings.

The exploratory analysis was conducted on data from a phase III study comparing CPX-351 with 7+3 for patients with secondary untreated AML. Overall, 34 of the 52 patients (65%) in the CPX-351 arm who proceeded to transplant remained alive after a median follow-up of 521 days. In the 7+3 arm, after 442 days of follow-up, 13 of 39 patients remained alive (33%).

From the time of transplant, the median overall survival (OS) was not reached in the CPX-351 arm versus 10.25 months for 7+3, representing a 54% reduction in the risk of death (HR, 0.46; 

 = .0046). Furthermore, 100 days after transplant, the rate of mortality from any cause was 53% lower in the CPX-351 arm versus 7+3.

"A greater proportion of patients treated with CPX-351 versus 7+3 in both age subgroups eventually went on to receive an allogeneic transplant," said Jeffrey E. Lancet, MD, from the Moffitt Cancer Center, during the presentation. "We believe that these results may indicate CPX-351 could provide a potential bridge to successful allogeneic transplant in an otherwise poor-risk group of AML patients, keeping in mind that these results should be interpreted with caution as they do represent an exploratory analysis of a non-randomized subgroup of a larger phase III trial."

CPX-351 is a liposomal bound coformulation of cytarabine and daunorubicin which delivers the two medications in a 5:1 molar ratio. The phase III trial consisted of 309 patients aged 60 to 75 who were stratified evenly between each arm into groups aged 60 to 69 (n = 198) or from 70 to 75 (n = 111). Patient characteristics were well-balanced between the 2 arms and groups.

Findings from the full cohort of patients in the study showed a 3.61-month improvement in OS for CPX-351 versus 7+3 (HR, 0.69; 

 = .005). The complete response (CR) or CR with incomplete platelet or neutrophil recovery (CRi) rate was 47.7% versus 33.3% for CPX-351 and 7+3, respectively (OR, 1.77; 95% CI, 1.11-2.81; 

"In this phase III trial, CPX-351 was associated with a significantly longer median OS and higher response rates compared with 7+3 in patients over age 60 with newly diagnosed, high-risk or secondary AML," noted Lancet.

More patients in the CPX-351 arm went on to receive a stem cell transplant (34% versus 25%); however, this difference was not statistically significant (OR, 1.54; 95% CI, 0.92-2.56; 

 = .098). When looking at age demographics for those who received transplant, significantly more patients aged 70 to 75 years could proceed to transplant in the CPX-351 arm versus 7+3 (28.1% vs 11.1%; OR, 3.12; 95% CI, 1.12-3.72).

Overall, in the age 60 to 69 group, there were 36 patients in the CPX-351 arm and 33 in the 7+3 arm who proceeded to transplant. In those aged 70 to 75, there were 16 in the CPX-351 arm and 6 in the 7+3 group. In the younger group, approximately 55% of patients were male and most had an ECOG performance status of 0 to 1 (94%). In the older age group, the population consisted more heavily of males (77%). AML subtypes and karyotypes were well balanced between the groups.

"Overall, the survival of transplanted patients was longer in patients treated with CPX-351 versus 7+3, although in the 70 to 75 subgroup this difference did not quite reach statistical significance," noted Lancet.

 mutations appeared to respond better to treatment with CPX-351. In this population, those treated with CPX-351 (n = 22) had a CR or CRi of 68.2%, and 45% went on to receive a transplant. In the 7+3 group of 

-mutant AML (n = 20), the CR plus CRi rate was 25% and 10% proceeded to transplant.

 mutation, a higher percentage achieved a CR or CRi with CPX-351 versus 7+3. Not surprisingly, probably because of this, a higher proportion of patients with 

 went on to transplant, if they received CPX-351 as their initial therapy," said Lancet.

The analysis looked at the safety profiles prior to transplant for those in the CPX-351 arm (n = 52) and 7+3 (n = 38). There were differences in infection and bleeding events in the CPX-351 arm that delayed recovery from myelosuppression, Lancet noted. Eighty-five percent of those in the CPX-351 arm experienced febrile neutropenia versus 71% of those in the 7+3 group. Additionally, the epistaxis rates were 38% versus 24%, for CPX-351 and 7+3, respectively.

The adverse events for each agent remained consistent in the 60 to 69 age group and those aged 70 to 75. "When we did the same analysis based on the age breakdown, there really was no significant difference in the safety profile for CPX-351 in the transplant patients in the different age subgroups," said Lancet.

Based on data from the full study, the FDA granted CPX-351 a breakthrough therapy designation in May 2016 as a treatment for patients with therapy-related AML or AML with myelodysplasia-related changes. Final OS data from the phase III study were initially presented at the 2016 ASCO Annual Meeting. The company developing the treatment, Jazz Pharmaceuticals, is working to complete a new drug application.

Lancet JE, Uy GL, Cortes J, et al. Analysis of Transplantation Rate and Overall Treatment Efficacy By Age for Patients Aged 60 to 75 with Untreated Secondary Acute Myeloid Leukemia (AML) Given CPX-351 Liposome Injection Versus Conventional Cytarabine and Daunorubicin in a Phase III Trial. Presented at: BMT Tandem Meetings; February 22-26, 2017; Orlando, FL. Abstract 19.

In the age 60 to 69 group, the median OS from the time of transplant was not reached in the CPX-351 arm versus 12.16 months with 7+3 (HR, 0.49; 95% CI, 0.24-0.98; 

 = .02). In the aged 70 to 75 arm, the median OS was not reached with CPX-351 versus 6.64 months with 7+3 (HR, 0.22; 95% CI, 0.04-1.23; 

More patients with acute myeloid leukemia could proceed to transplant following treatment with CPX-351 compared with the traditional 7+3 chemotherapy regimen.

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