Conditioning Regimen Intensity May Affect Outcome in MDS Patients Undergoing Allogeneic Stem Cell Transplantation, Depending on MDS Subgroup

Allogeneic stem cell transplantation (SCT) is a potentially curative treatment for MDS. Besides the innate heterogeneity of MDS, intensity of the conditioning regimen (myeloablative (MAC) versus reduced intensity/non-myeloablative (RIC)), specific agents used in conditioning, donor and source of stem cells and GVHD prevention regimens further influence outcomes. We sought to determine how conditioning regimens influenced MDS subgroup cohort outcomes. We retrospectively analyzed outcomes of 107 MDS patients (63 male and 44 females) with median age 61.8 (17-73 years) who underwent allogeneic SCT at our institution between 2008 and 2017. For the purposes of this report, patients were grouped according to WHO classification into non-RAEB (RCMD, RA, RARS RCUD or 5q deletion, n=49) and RAEB (RAEB1 and RAEB2, n=58) categories. Median time from MDS diagnosis to transplantation was 139 days (20-3175). No patients were in complete remission (CR) at time of SCT. Allogeneic donor types were matched related, matched unrelated, haplo-identical and cord blood in 30, 65, 10 and 2 patients, respectively. Stem cell source was peripheral blood (91 patients) and bone marrow in 14. Forty patients (median age 52.2 (17-61) years) underwent MAC and 67 (median age 63.7 (23-73) years) RIC. Twelve patients died within 100 days of transplantation, 3 due to disease progression, 5 to acute GVHD, and 4 to other transplant-related causes. Median overall survival (OS) for all 107 patients was 1.3 years with 54%, 47% and 40% alive at 1, 2 and at 5 years. OS was slightly higher in patients undergoing RIC with OS of 57%, 48% and 40% (median 1.532 years) versus 50%, 40% and 38% with MAC (median 0.92 years) at the same time points (p>0.1). Median OS of the 49 patients with non-RAEB and 58 patients with RAEB MDS was 3.01 years versus 0.92 years (p>0.1). GVHD was the most frequent cause of death (46%), followed by relapse/progression (28%), infection (14%) and other (12%). Of 29 patients undergoing RIC with non-RAEB MDS, median OS was 3.78 years while for 38 RAEB patients it was 1.17 years (p>0.1). See table for OS according to conditioning regimen and WHO classification. For MAC, in 20 non-RAEB patients median OS was 2.2 years while the median OS was 0.69 years for 20 RAEB patients (p>0.1). CR after SCT was achieved in 57 patients (53%), 33 receiving RIC (CR 49.2%) and 24 receiving MAC (CR 60%). Seven patients subsequently relapsed, 4 RIC and 3 MAC. Of the non-RAEB patients achieving CR, median OS in the 16 patients treated with 111 RIC was not reached and in 14 patients receiving MAC, median OS was 3.75 years (p>0.1). For the 27 RAEB patients achieving CR, median OS was 4.4 years in 17 patients treated with RIC versus not reached in 10 patients treated with MAC. Overall, death in non-RAEB patients occurred in 26/49 (53%) compared to 38/58 (66%) RAEB patients and in 40/67 (59%) patients undergoing RIC versus 25/40 (63%) MAC patients (p>0.5). The hematopoietic transplant comorbidity index did not predict OS outcomes in these MDS patients (p>0.1) and the cytogenetic score according to the IPSS-R "very good -very poor" groups indicated no differences in OS in the non-RAEB patients but in RAEB patients significant differences according to the cytogenetic score was evident (P<0.01). Conclusions: In this retrospective analysis of MDS patients undergoing allogeneic SCT, achieving CR led to improved survival. In non-RAEB MDS patients achieving CR, OS was similar irrespective of conditioning intensity (RIC or MAC). Furthermore, outcomes did not differ in RAEB patients who achieved CR according to intensity of conditioning regimen. However, those receiving MAC had not reached median OS at 5 years. The outcomes in this analysis indicate that improvement in the incidence of deaths due to GVHD would likely have the greatest impact in improving survival in MDS patients undergoing allogeneic transplantation. Table Disclosures Abhyankar: Therakos: Other: Consulting, Speakers Bureau; Incyte: Speakers Bureau. Lin:Jazz Pharmaceuticals: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Yacoub:Incyte: Consultancy, Speakers Bureau. Ganguly:Kite Pharma: Honoraria, Other: Advisory Board; Seattle Genetics: Speakers Bureau; Janssen: Honoraria, Other: Advisory Board; Daiichi Sankyo: Research Funding. McGuirk:Pluristem Ltd: Research Funding; Gamida Cell: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bellicum Pharmaceuticals: Research Funding; Astellas: Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation.

Download Full-text

Allogeneic Stem Cell Transplantation in First Chronic Phase CML during the Last Decade: Retrospective Analysis of the National SFGM-TC Registry

Blood ◽

10.1182/blood.v128.22.3476.3476 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3476-3476

Author(s):

Franck-Emmanuel Nicolini ◽

Valerie Coiteux ◽

Gerard Socie ◽

Didier Blaise ◽

Eric Deconinck ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Research Funding ◽

Conditioning Regimen ◽

Chronic Phase ◽

Advisory Committees ◽

Second Period

Abstract Background & aims The only curative treatment of CML to date, remains allogeneic stem cell transplantation (Allo-SCT) despite some observations of non-detectable disease recurrence after tyrosine kinase inhibitor (TKI) cessation. The scope of allogeneic stem cell transplant for chronic phase (CP-) CML remains debatable and it seems interesting to retrospectively analyse the settings of this procedure in such patients since the introduction of TKI within the therapeutic arsenal of this disease. Methods We retrospectively analysed the registry of the Francophone society of stem cell transplantation and cellular therapy (SFGM-TC) from 2002 to 2014, for patients being in CP at diagnosis and at transplant. All data were captured according to thefrench regulations and were collected after signed up informed consent for each patient. All patients were transplanted for different degrees of resistance or severe recurrent intolerance to TKI(s). We segmented the observation period into two parts: 2002-2006 (Imatinib era) and 2006-2014, once second generation TKI were available in our country (TKI2 era). All patients were in CP-CML at diagnosis and first chronic phase at transplant. Second transplants for the same patient were excluded from this analysis. Results From 2002 to 2014 the proportion of transplants for CML dramatically decreased form 7.1% to <3% of totalallo-SCT performed in the country. Nevertheless, between 2002 and 2014, 191 transplants were performed for CP-CML, 121 during the first period and 70 during the second period. Interestingly, age at transplant is 36 (26-43) for IM period and older, 44 (26-55) years for TKI2 period; with a sex ratio of 1.08 and 1.3 respectively (p=ns). The median interval between diagnosis and transplant was 19 (1.4-197) months for IM period and much longer thereafter[32 (6.6-194) months, p<0.001]. The source of cells varied a lot with 71% of BM, 25.5% PBSC and 3.5% CB for IM period, 37% BM, 56% PBSC and 7% CB for TKI2 period (p<0.001), whereas the proportion of MAC versus RIC remained stable (88.5%/11.5% versus 81%/19%, p=0.262). The use of TBI as a part of the conditioning regimen was drastically reduced during the second period: 37% IM era, 14% TKI2 era (p<001). While ABO match did not differ, the use of unrelated donors largely increased in the second period (66% versus 46%, p=0.015), with less identical sibling donors used (33% versus 52%) in this last period. The proportion of sex match did not differ with a majority of male to male transplants (28% and 37%; p=ns) performed in both groups. The majority of patients wereGratwohlscore 3 in IM period andGratwohlscore 4 in the second period. Overall, the cumulative incidence of grade 2-4 acute GVHD was 32%, 41.3% and 44% at 1,2 and 3 months respectively, and the overall cumulative incidence of chronic GVHD was 26%, 40%, 45%, 50% at 1, 2, 5, and 10 years. The TRM rates were not different between the 2 periods: 22.4%, 23%, 26.65% and 27.8% at 1, 2, 5 and 10 years for IM period and 16.2%, 19.7%, 22.4% and 27.8% at 1, 2, 5 years for TKI2 period (NR 10 year for this period, p=0.508).The overall (OS) and relapse-free survival (RFS) rates according to the two periods are shown in Figure 1, with only a trend in the improvement of OS and RFS in the TKI2 period (log-rank tests, p=0.601 and 0.651 respectively).Gratwohlscore efficiently segregated patients for OS (overall p value = 0.002) and RFS (p=0.007). Multivariate analysis adjusted on OS identified only age (HR=1.02, p=0.05), and a related donor as a favourable variable on outcome (HR=0.53, p=0.031) with no significant influence of age, interval diagnosis-allo-SCT, source of donor cells, and type of conditioning regimen. Conclusion Allo-SCT still remains a curative treatment of CP-CML despite significant toxicities over time and the picture of this procedure in the therapeutic arsenal has dramatically changed over the last decade due to multiple therapeutic options offered now. Despiteallo-SCT of patients with longer diseases histories, probably more co-morbidities, there is an encouraging trend in the improvement of OS and RFS. Figure 1 OS and RFS for CP-CML according to the engraftment period. Figure 1. OS and RFS for CP-CML according to the engraftment period. Figure 2 Figure 2. Disclosures Nicolini: BMS: Consultancy, Honoraria; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Coiteux:Novartis, BMS, ARIAD: Speakers Bureau. Michallet:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria. Peffault De Latour:Novartis: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding.

Download Full-text

The Effect of JAK 1/2 Inhibitors on Outcomes of Allogeneic Stem Cell Transplantation for Patients with Myelofibrosis

Blood ◽

10.1182/blood-2018-99-112769 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5784-5784

Author(s):

Guido Lancman ◽

Kathleen Miller ◽

Shuli Li ◽

Vincent T. Ho ◽

Amir T. Fathi ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Research Funding ◽

Acute Gvhd ◽

Advisory Committees ◽

Free Survival ◽

Donor Type

Abstract Introduction: Ruxolitinib was the first JAK 1/2 inhibitor (JAKi) approved for myelofibrosis (MF), with several other JAKi in development. Ruxolitinib was approved on the basis of reducing splenomegaly and improving constitutional symptoms, but its effect on subsequent allogeneic stem cell transplantation (SCT) is not well understood. Retrospective studies to date have reported mixed outcomes after SCT for MF patients with previous exposure to JAKi. In this multicenter retrospective study, we report on outcomes of patients with MF treated with SCT at our institutions. Methods: We analyzed outcomes for 184 consecutive patients at three institutions who underwent SCT for primary or secondary MF. Primary outcomes included overall survival (OS), progression free survival (PFS), and graft-versus-host-disease (GVHD)-free and relapse-free survival (GRFS), all measured from the time of SCT. Cox proportional hazard regressions were fit to estimate the association between the use of JAK 1/2 inhibitors prior to SCT and OS, PFS, and GRFS, adjusting for donor type and DIPSS-plus status. p<0.05 was considered statistically significant. Results: 72 patients received a JAKi prior to SCT, while 112 did not. Patients in these two groups were well-matched with respect to age, sex, DIPSS plus score, conditioning, and donor type (Table 1). Median follow-up was 31.2 months (range: 0.8-146.3 months). In univariate analysis, there was no difference in OS (JAKi: 4-yr OS 56.7% [95% CI 40.9-69.8%] vs. no JAKi: 43.6% [95% CI 32.9-53.9%], p=0.49), PFS (JAKi: 4 yr PFS 54.1% [95% CI 40.8-65.7%] vs. no JAKi: 43.9% [95% CI 33.4-53.9%], p=0.77), or GRFS (JAKi: 8-month GRFS 56.6% [95% CI 44.1-67.4%] vs. no JAKi: 50.4% [95% CI 40.4-59.5%], p=0.62) in the overall population; there was similarly no difference when comparing only intermediate-risk or only high-risk patients. In multivariate analysis, there was no difference in these outcomes for patients based on previous JAKi exposure when accounting for DIPSS plus score and donor type (related vs unrelated). Rates of acute GVHD were similar between the two groups (JAKi: 53.5% vs. no JAKi: 55.0%, p=0.88), including grade 3 or 4 acute GVHD (JAKi: 16.9% vs no JAKi: 19.8%, p=0.70). Conclusions: Our data suggest that there is no statistically significant difference in OS, PFS, GRFS, or rates of acute GVHD after SCT for MF patients based on previous JAKi treatment. This was true overall and after adjusting for DIPSS plus risk score or donor type. Given the retrospective design of our study, we were not able to assess prior response to JAKi or splenomegaly at SCT, which may influence outcomes. Given mixed results in the literature to date, we eagerly await the results of ongoing phase 2 trials of JAKi prior to SCT for MF. Disclosures Ho: Jazz Pharmaceuticals: Consultancy. Fathi:Astellas: Honoraria; Jazz: Honoraria; Boston Biomedical: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Agios: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria. Chen:Takeda Pharmaceuticals: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Consultancy; REGiMMUNE: Consultancy. Hoffman:Formation Biologics: Research Funding; Incyte: Research Funding; Janssen: Research Funding; Merus: Research Funding; Summer Road: Research Funding. Mascarenhas:Novartis: Research Funding; Merck: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Promedior: Research Funding; Janssen: Research Funding; Roche: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

Intensified Cytarabine Dose during Consolidation Therapy in AML Patients Under 65 Years Is Not Associated with Survival Benefit

Blood ◽

10.1182/blood-2021-146606 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1242-1242

Author(s):

Maher Hanoun ◽

Leo Ruhnke ◽

Michael Kramer ◽

Kerstin Schäfer-Eckhard ◽

Björn Steffen ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Research Funding ◽

High Dose ◽

Advisory Committees ◽

Disease Characteristics ◽

First Remission

Abstract Background: Acute myeloid leukemia (AML) is characterized by a high relapse rate, indicating insufficient clearance of leukemia-initiating cells. Depending on genetic risk stratification, consolidating chemotherapy proves to significantly reduce the risk of relapse. In particular, in younger AML patients higher dosage of cytarabine appears to improve long-term outcome, while there is no apparent benefit of multiagent combination, compared to cytarabine monotherapy. However, to this end the optimal dosage of single agent cytarabine in consolidation therapy after 7+3 remission induction remains elusive. Methods: Here, we retrospectively assessed the impact of different dosages of cytarabine consolidation on outcome in a large real-world data set from the German Study Alliance Leukemia-Acute Myeloid Leukemia (SAL-AML) registry. Patients below 65 years of age, registered between April 2005 and September 2020 with non-acute promyelocytic leukemia, who attained complete remission after intensive induction and received at least one consolidation cycle with intermediate (IDAC) or high dose cytarabine (HiDAC) were selected. To account for differences in patient and disease characteristics between both groups, the average treatment effect was estimated by propensity score weighting. Results: 642 patients received HiDAC consolidation with a median dosage of 5794.88 (IQR, 4745.48-5971.56) mg/m 2/d with a median number of 3 cycles (IQR, 2-3), whereas 178 patients received IDAC consolidation with 1946.16 (IQR, 1869.51-2469.15) mg/m 2/d with a median of 2 cycles (IQR, 1-3). IDAC-treated patients showed in average a higher age (median (IQR) 58.5 (49-62) years vs. 50 (41-56) years) and more comorbidities with 43.8% having an HCT-CI score of 2-4, compared to 22.3% among HiDAC-treated patients. Alongside, significantly more secondary (5.1% vs. 3.1%) and therapy-related (12.4% vs. 4.1%) AML as well as more adverse (14.5% vs. 6.5%) and less favorable (40.6% vs. 56%) genetic risk features according to ELN 2017 risk classification were found among IDAC-treated patients. After propensity score weighting for differences in patient and disease characteristics, overall survival after 5 years was comparable between HiDAC-treated (71.1 %) and IDAC-treated (67.7%) patients. Moreover, no significant differences in relapse-free survival were observed after 5 years (47.4 vs. 45.2%). Notably, more patients treated with IDAC received allogeneic stem cell transplantation in first remission (37.6 vs. 19.8%) while significantly more HiDAC-treated patients underwent allogeneic stem cell transplantation in relapse (30.8 vs. 20.2%). Censoring for allogeneic stem cell transplantation in first remission revealed no significant survival difference with regard to cytarabine dosage. Considering only ELN favorable risk AML patients, there was no difference in 5-years overall (80.5% vs. 83.9%) nor relapse-free (57.7% vs. 56.8%) survival. Of note, significantly more patients treated with HiDAC suffered from ≥3 CTCAE infectious complications (56.7 vs. 44.1%), which was more striking in patients above 50 years of age. The rate of other ≥3 CTCAE non-hematological toxicities and secondary malignancies was comparable in both treatment groups. Conclusion: This retrospective analysis suggests no significant benefit of high dose cytarabine compared to intermediate dosages in consolidation for AML patients under 65 years of age, independent of ELN risk group. Disclosures Krause: Siemens: Research Funding; Takeda: Honoraria; Pfizer: Honoraria; art-tempi: Honoraria; Kosmas: Honoraria; Gilead: Other: travel support; Abbvie: Other: travel support. Schliemann: Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Other: travel grants; Astellas: Consultancy; AstraZeneca: Consultancy; Boehringer-Ingelheim: Research Funding; BMS: Consultancy, Other: travel grants; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Haenel: Jazz: Consultancy, Honoraria; GSK: Consultancy; Bayer Vital: Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Brummendorf: Takepart Media: Honoraria; Repeat Diagnostics: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Patents & Royalties, Research Funding; Janssen: Honoraria; Bristol Myers: Research Funding. Fransecky: Abbvie: Honoraria, Research Funding; Medac: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Einsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding. Held: MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Roche: Research Funding; Acortech Biopharma: Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Platzbecker: Janssen: Honoraria; Celgene/BMS: Honoraria; AbbVie: Honoraria; Geron: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Baldus: Amgen: Honoraria; Celgene/BMS: Honoraria; Novartis: Honoraria; Jazz: Honoraria. Mueller-Tidow: Janssen Cilag: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bioline: Consultancy, Research Funding.

Download Full-text

Reduced Intensity Stem Cell Transplantation for Accelerated-Phase Myelofibrosis

Blood ◽

10.1182/blood-2021-152712 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 314-314

Author(s):

Nico Gagelmann ◽

Anita Badbaran ◽

Markus Ditschkowski ◽

Victoria Panagiota ◽

Bruno Cassinat ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Research Funding ◽

Continuous Variable ◽

Advisory Committees ◽

Reduced Intensity

Abstract Background Circulating peripheral blasts ≥1% have long been considered an unfavorable feature for patients with primary myelofibrosis. Recent findings (Masarova et al. Cancer 2020) suggested more differentiated impact of blasts on outcome. However, accelerated-phase (AP) myelofibrosis, which is currently defined by circulating blasts 10-19%, usually confers worse outcome. The outcome of allogeneic stem cell transplantation for AP myelofibrosis has not been evaluated yet. Patients and Methods Thirty-five out of 349 patients with primary or secondary myelofibrosis undergoing reduced intensity allogeneic stem cell transplantation were reported as AP (10-19% blasts) at time of transplantation. Outcome of these patients was compared to patients with circulating blasts: 0% (n=135), 1-4% (n=146), and 5-9% (n=33). Conditioning consisted of busulfan/fludarabine, fludarabine/melphalan, or fludarabine/TBI2Gy. Results Characteristics. The median blast percentage in the AP group was 14% (10-19%). More patients in the AP group appeared to have secondary myelofibrosis (40%) compared with patients with the 0% blasts (21%), the 1-4% blasts (31%), and 5-9% blasts group (30%, P=0.08). The median hemoglobin levels decreased with blast group: 9.7g/dl (0%), 9.5g/dl (1-4%), 9.4g/dl (5-9%), and 9.0g/dl (AP). In contrast, median leukocyte counts appeared to be increased: 7.2, 9.5, 16.9, and 13.6 x 10 9/l, respectively. More patients in the AP group presented with constitutional symptoms (71%). There was no difference in frequency of driver mutations (P=0.57) and presence of high-risk mutation profile (defined as ASXL1, SRSF2, IDH1/2, EZH2; P=0.93). Most patients in each group received matched unrelated donor transplants (P=0.61). Survival. The median follow-up of all patients was 6 years. Follow-up was similar across the 4 groups (P=0.30). 5-year overall survival (95% confidence interval) according to blast group was 66% (58-73%) for the 0%, 62% (53-71%) for the 1-4%, 66% (50-81%) for the 5-9%, and 68% (53-83%) for the AP group (P=0.92). Median overall survival was not reached for all groups, except for 1-4% blasts group (17.1 years). 10-year long-term follow-up showed survival rates of 64% for the 0%, 58% for the 1-4%, 66% for the 5-9%, and 68% for the AP group. In terms of relapse-free survival, 5-year outcome was comparable (P=0.95) showing 57% (48-66%) for the 0%, 52% (43-60%) for the 1-4%, 55% (37-73%) for the 5-9%, and 52% (34-69%) for the AP group. Median relapse-free survival was 7.9 years, 5.7 years, 6.5 years, and 9.2 years, respectively. Taking blasts as continuous variable in spline function analyses on survival, no significant effect was identified overall, while after 15% blasts, risk for death appeared to increase consistently. Non-relapse mortality and relapse. In terms of non-relapse mortality, no difference was found between the groups (P=0.33). 5-year outcome was 25% (19-31%) for the 0%, 33% (25-40%) for the 1-4%, 31% (15-47%) for the 5-9%, and 17% (5-30%) for the AP group. In terms of cumulative incidence of relapse, the AP group showed 5-year outcome of 31% (15-47%) compared to 18% (12-24%) for the 0%, 16% (10-22%) for the 1-4%, and 14% (1-28%) for the 5-9% group (P=0.17). Pairwise comparison showed significant difference between AP and the other groups (P=0.03). Spline function analyses using blasts as continuous variable and 3 knots showed no significant effect on non-relapse mortality but suggested increased risk of relapse for AP myelofibrosis (P=0.04). Multivariable analysis. Adjusting for clinical (diagnosis, leukocyte and platelet counts, age, constitutional symptoms) and molecular-genetic (driver mutation genotype, high-risk mutations), Cox model on survival (with the 0% group as reference) showed comparable risk of death across blast groups with hazard ratios of 1.06 (0.70-1.62) for the 1-4%, 1.11 (0.56-2.32) for the 5-9%, and 0.95 (0.49-1.86) for the AP group. Independent factors for worse outcome were age, platelet and leukocyte counts, and CALR/MPL-unmutated genotype. Conclusion Reduced intensity allogeneic stem cell transplantation for AP myelofibrosis was associated with excellent and similar survival and non-relapse mortality in comparison with other blast groups and after adjustment for other risk factors, offering long-term survival (>10 years) for more than half of patients at AP. Relapse incidence appeared to be increased for AP myelofibrosis. Disclosures Heuser: Karyopharm: Research Funding; Tolremo: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; BergenBio: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Pharma AG: Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Thol: Pfizer: Honoraria; Abbvie: Honoraria; Astellas: Honoraria; BMS/Celgene: Honoraria, Research Funding; Jazz: Honoraria; Novartis: Honoraria. Scott: Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Kroeger: Neovii: Honoraria, Research Funding; Sanofi: Honoraria; Jazz: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Gilead/Kite: Honoraria; AOP Pharma: Honoraria; Novartis: Honoraria.

Download Full-text

Characteristics of DNMT3A-R882 Mutation in AML

Blood ◽

10.1182/blood-2018-99-116652 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5263-5263

Author(s):

Olga Blau ◽

Franziska Behrenbeck ◽

Mirgul Bayanova ◽

Igor-Wolfgang Blau ◽

Lars Bullinger

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Standard Therapy ◽

Research Funding ◽

Advisory Committees ◽

Mutation Burden

Abstract Introduction Genetic mutations play an important role in the development and progression of acute myeloid leukemia (AML). One of the common aberration in AML is mutation in the epigenetic modifying gene, DNA methyltransferase 3α (DNMT3A). Despite the active investigations, the exact impact of mutation on the development of AML is not completely known. The occurrence of mutation in pre-leukemic cells explains a particular attention to DNMT3A. The most common mutation is located in codon R882 (DNMT3AR882mut). The objective of this study is to compare clinical and prognostic characteristics of AML patients in relation to presence of DNMT3AR882mut. The quantification of the mutation burden in follow up samples was performed both after standard therapy and after allogeneic stem cell transplantation (alloSCT). In addition, it was investigated whether the quantification of the mutational burden of DNMT3AR882mut is significant to the progression of disease. Methods Samples of 580 AML were retrospective analyzed using HRM-PCR, capillare electrophorese, and Sanger Sequencing. The median observation period was 495 days. Of 580, 69 have DNMT3AR882mut. Mutation burden was evaluated in follow-up samples by quantitative PCR. The statistical methods were selected according to sample distribution and evaluated with SPSS (significance level p <0.05). Results DNMT3A R882mut were associated with a higher level of leukocytes and blasts at diagnosis, with M4-M5 variant of AML, and with normal karyotype. It was found that NPM1 and FLT3-ITD are more frequent co-mutations that have a significant effect on the prognosis of disease. Analysis of mutation burden of DNMT3AR882mut at diagnosis showed a large spread (0.02 - 66.9 %). At the time of diagnosis, DNMT3AR882mut transcript levels did not correlate with clinical and prognostic characteristics. The mutation burden decreased after therapy, but was always visible in CR after standard therapy. In CR after allogeneic stem cell transplantation (alloSCT) with complete donor chimerism mutation was not detected. In relapse of AML, an increasing of the mutation burden were found in all patients, both after therapy, and after alloSCT. In relapse samples, the same mutant clone was found. Conclusion The DNMT3A mutation is a common genetic aberration in AML patients, which is associated with specific clinical and prognostic data. The presence of co-mutations, especially NPM1 and FLT3-ITD, has a significant effect on the prognosis of patients. Quantitative detection of DNMT3AR882mut at different time points of disease revealed the persistence of mutated clone after standard therapy and disappearance of DNMT3AR882mut after alloSCT. It is suggest that alloSCT is the optimal treatment option for the eradication of DNMT3AR882mut in AML patients. Disclosures Bullinger: Sanofi: Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Pfizer: Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Bayer Oncology: Research Funding.

Download Full-text

Impact of TP53 gene Mutation Clearance and Conditioning Intensity on Outcome in MDS or AML Patients Prior to Allogeneic Stem Cell Transplantation

Blood ◽

10.1182/blood-2019-131530 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 149-149 ◽

Cited By ~ 2

Author(s):

Onyee Chan ◽

Anthony Hunter ◽

Chetasi Talati ◽

David A Sallman ◽

Hannah Asghari ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Research Funding ◽

Tp53 Mutation ◽

Prognostic Impact ◽

Advisory Committees ◽

Conditioning Intensity

Background: Tumor protein 53 (TP53), located on the short arm of chromosome 17, is an important tumor suppressor gene responsible for critical regulatory functions. There is existing controversy regarding the role of allogeneic stem cell transplantation (allo-SCT) in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) harboring a TP53 mutation. While most studies report increased relapse and poor survival after allo-SCT with TP53 mutated AML or MDS, (Bajar et al., JCO 2014; Lindsley et al., 2017) others found no influence of TP53 mutation on allo-SCT outcomes (Aldoss et al., 2017). Notably, previous studies have predominantly evaluated the prognostic impact of TP53 mutation at the time of diagnosis and not serially in response to treatment. In this study, we aim to clarify the prognostic impact of TP53 mutation clearance prior to allo-SCT in patients with TP53 mutated AML or MDS. Methods: Data was obtained and analyzed on MDS or AML patients who received allo-SCT at the Moffitt Cancer Center (2013-2018) and had presence of TP53 at least once after diagnosis and prior to allo-SCT. TP53 clearance was defined by last next-generation sequencing (NGS) test prior to allo-SCT demonstrating no TP53 mutation with a variant allele frequency (VAF) greater than 5%. We utilized clinical data captured by BMT Research and Analysis Information Network (BRAIN). Univariate and multivariate analyses were conducted using log-rank and Cox regression, respectively. Kaplan-Meier analysis with log-rank test was used to estimate relapse free survival (RFS) and median overall survival (OS) from the time of allo-SCT. Cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were performed as defined by the Fine and Gray model. Results: We identified 47 patients (29 males/18 females) with TP53 mutation prior to allo-SCT with primary diagnosis of AML (55.3%) or MDS (44.7%) (Table 1). The median follow-up was 25.4 months with 2-year OS of 32.8% for the entire cohort. The median age at diagnosis was similar between TP53-cleared and TP53-persistent groups with 68% of the patients >= 60 years at the time of allo-SCT. Only 26% (n=12) had clearance of their TP53 mutation prior to allo-SCT. The majority of the patients had complex cytogenetics at diagnosis (85%) with deletion 5q being the most common coexisting aberration (75% in TP53-cleared and 68.6% in TP53-persistent, p=NS). Patients with TP53 clearance received hypomethylating agent (HMA) as frontline treatment more frequently compared to those with persistent TP53 (66.7% vs. 45.7%, p=NS). They also had fewer lines of therapy (83.3% with 1 line vs. 62.9%, p=NS), and a higher rate of complete response prior to allo-SCT (83.3% vs. 57.1%, p=NS). Amongst patients receiving HMA as frontline therapy (n=24), we observed significantly better survival in TP53-cleared patients compared to those with persisted TP53 (median OS of 21.73 months vs. 6.44 months, p=0.042) (Figure 1). Myeloablative conditioning (MAC) regimen was used in 33.3% of TP53-cleared in comparison to 42.9% in TP53-persistent cohort (p=NS). Median OS was 21.7 months for patients with clearance of TP53 vs. 8.1 months for those with persistent TP53 at allo-SCT; although it did not meet statistical significance (p=0.106). MAC compared to reduced intensity conditioning (RIC) regimen resulted in significantly worse RFS (HR 2.06, 95% CI 1.04-4.12, p=0.040) and OS (HR 2.70, 95% CI 1.30-5.60, p=0.008). Conditioning intensity was the only factor that significantly influenced RFS and OS outcomes (Table 2). When repeating these analyses separately on the TP53-cleared and TP53-persistent groups, only the latter remained significant for conditioning (MAC, univariate OS: HR 2.6, 95% CI 1.14-5.92, p=0.023). Conclusions: TP53 clearance at the time of allo-SCT is predictive of better outcomes in patients who had frontline HMA therapy. For patients with persistent TP53 at the time of allo-SCT, those received MAC experienced worse outcomes compared to RIC in this cohort. The OS at 2-year for TP53-persistent patients is over 30% suggesting even these patients can potentially benefit from transplantation. Disclosures Talati: Celgene: Honoraria; Agios: Honoraria; Pfizer: Honoraria; Astellas: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Sallman:Abbvie: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Research Funding; Incyte: Speakers Bureau; Celyad: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau. Bejanyan:Kiadis Pharma: Other: advisory board. Kuykendall:Celgene: Honoraria; Incyte: Honoraria, Speakers Bureau; Janssen: Consultancy; Abbvie: Honoraria. Padron:Incyte: Research Funding. Komrokji:Incyte: Consultancy; Agios: Consultancy; JAZZ: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau; celgene: Consultancy; DSI: Consultancy; pfizer: Consultancy. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy. Sweet:Incyte: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Stemline: Consultancy; Pfizer: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Phase I/II Study of the Deacetylase Inhibitor Panobinostat As Maintenance Therapy after an Allogeneic Stem Cell Transplantation in Patients with High-Risk MDS or AML: The Panobest-Trial

Blood ◽

10.1182/blood.v126.23.4344.4344 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4344-4344 ◽

Cited By ~ 11

Author(s):

Gesine Bug ◽

Andreas Burchert ◽

Eva-Maria Wagner ◽

Nicolaus Kroeger ◽

Zuzana Jedlickova ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Research Funding ◽

Hematologic Toxicity ◽

Advisory Committees ◽

One Year

Abstract Background: Leukemic relapse and graft-versus-host disease (GvHD) remain major obstacles after an allogeneic stem cell transplantation (HSCT). Panobinostat is a potent inhibitor of class I, II and IV deacetylases and has shown antileukemic as well as immunomodulatory activity. The hypothesis of our phase I/II PANOBEST trial was that panobinostat can effectively prevent relapse in patients (pts) with high-risk (HR) myeloid diseases while simultaneously reducing GvHD. We aimed to determine dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of panobinostat in adult pts with HR acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) in complete hematologic remission (CR) after a reduced-intensity HSCT. Secondary objectives were evaluation of safety and tolerability of panobinostat, and overall (OS) and disease-free survival (DFS) at 1 and 2 years after HSCT. Methods: In two sequential schedules, panobinostat was administered orally thrice weekly, (TIW), either every week (A) or every other week (B). In schedule A, panobinostat was started at a dose of 10 mg TIW and escalated to 30 mg TIW using a 3+3 design; in schedule B, panobinostat was given at doses of 20-40 mg TIW. Panobinostat was initiated between day +60 and +150 after HSCT and given for up to 1 year. Eligibility criteria included: ANC ≥ 1,000/μL, platelets ≥ 75,000/μL, adequate organ function and no severe GvHD. DLT was defined as prolonged G4 hematologic toxicity or any non-hematologic toxicity ≥ G3 unrelated to disease progression or intercurrent illness within 28 days of the first panobinostat dose. Results: 42 pts (37 AML, 5 MDS) were enrolled, with a median age of 52 years (range, 21-71). Cytogenetics were classified as low (n=6), intermediate-1/2 (n=20) or adverse risk (n=16) according to ELN criteria. Panobinostat was started a median of 98 days (range, 60-147) after HSCT from a matched related (n=9), matched unrelated (n=24), mismatched unrelated (n=6) or haploidentical donor (n=3). The majority of patients (n=28, 67%) were transplanted with active disease (bone marrow blasts 0-80%, median 21%, 1 pt. with extramedullary AML), 9 in CR1 (21%) and 5 in CR2 (12%). Patient and transplant characteristics were equally distributed between schedules A and B. Of 42 pts, 22 (54%) have completed one year of panobinostat, 1 remains on treatment and 19 (46%) discontinued prematurely after a median of 70 days (range, 12-342) due to adverse events (AEs) (n=10), relapse (n=6), patient decision (n=2) or prohibited comedication (n=1). To date, 24 out of 42 patients experienced panobinostat-related grade 3/4 AEs (schedule A: n=14, 67%; schedule B: n=10, 48%). The most common AEs were hematologic toxicity (G3: 14 pts, 33%; G4: 2 pts, 5%), constitutional (G3: 7 pts, 17%) and gastrointestinal symptoms (G3: 5 pts, 12%). Neurological AE and pain (G3, 2 pts each, 5%) as well as metabolic/laboratory alterations (G3: 3 pts., 7%) and renal toxicity (G3, 1 pt, 5%) were also reported. AEs were fully and rapidly reversible after interrupting panobinostat (n=24); 14 patients needed dose adjustment and no study-related deaths occurred. The RP2D was 20 mg TIW in arm A and 30 mg TIW every other week in arm B based on 5 DLTs: fatigue G3 at 20 mg, colitis and nausea/emesis G3 each at 30 mg (arm A), diarrhea and headache G3 at 40 mg each (arm B). Prophylactic or preemptive donor lymphocyte infusions (median 2, range, 1-6) were administered to 10 pts (42%, median 1.5x106 CD3+ cells/kg) in arm A and 8 pts (33%, median 0.5x106 CD3+ cells/kg) in arm B. Cumulative incidence (CI) of moderate (n=8) or severe (n=2) chronic GvHD was 24±0.4% at one year after HSCT and did not differ between both arms. There was no evidence of impaired immune reconstitution. To date, median OS and DFS have not been reached after a median follow up of 22 months (range, 6-57). At two years after HSCT, 5 patients have died from relapse (n=3), sepsis (n=1) or sudden death (n=1 at 3.5 months after study discontinuation) and CI of relapse was 21±0.5%, resulting in probabilities for 2-year OS and DFS of 88±5% and 74±7%, resp. Discussion: Panobinostat maintenance following HSCT for high-risk AML or MDS is feasible with a RP2D dose of 20 mg TIW weekly or 30 mg TIW every other week and associated with a low relapse rate. This provides a rationale for a prospective randomized trial of panobinostat as post-transplant intervention. Disclosures Bug: NordMedica: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Other: Travel grants, Research Funding; Novartis Oncology: Honoraria, Other: Travel grants, Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Astellas: Other: Travel grant; TEVA Oncology: Other: Travel grant; Gilead: Honoraria. Off Label Use: Panobinostat has not been approved for maintenance therapy after an allogeneic stem cell transplantation in ANL and MDS patients . Burchert:Bristol Myers Squibb: Honoraria. Bader:Neovii: Other: Institutional grants; Medac: Other: Institutional grants; Amgen: Consultancy; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Riemser: Other: Institutional grants. Ottmann:Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Prospective Analysis of Bortezomib, Fludarabine and Melphalan As Conditioning Regimen Prior to Allogeneic Stem Cell Transplantation for Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-117313 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1020-1020

Author(s):

Phyllis McKiernan ◽

David S Siegel ◽

David H. Vesole ◽

Tracy Andrews ◽

Noa Biran ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Conditioning Regimen ◽

Advisory Committees ◽

Significant Difference ◽

Grade 3

Abstract Background: Despite advances in novel myeloma treatments and autologous hematopoietic stem cell transplantation (ASCT), allogeneic HSCT (alloSCT) remains the only curative option for patients (pts) with multiple myeloma (MM). Questions remain as to the timing of alloSCT, toxicity risks and optimal conditioning regimen. The addition of bortezomib (Vel) to fludarabine (Flu) and melphalan (Mel) for conditioning prior to alloSCT is based on the demonstrated safety of Vel in combination with melphalan prior to ASCT, the synergistic effect of Vel with Mel, and the ability of Vel to selectively eliminate allo-reactive T-cells. Methods: We present a prospective Phase II study using Flu/Mel/Vel (FMV) as a conditioning regimen for alloSCT. The primary endpoint is overall survival (OS), and secondary endpoints include progression free survival (PFS), incidence of graft-versus-host disease (GVHD) and transplant related mortality (TRM). For related donors, the conditioning regimen was Flu 30 mg/m2 days -5, -4, -3, -2, Vel 1.6 mg/m2 days -4, -1, Mel 140 mg/m2 day -2. For unrelated donors, rabbit ATG 4 mg/kg was given in divided doses days -3, -2, -1. GVHD prophylaxis consisted of methotrexate and tacrolimus. We compared pts receiving FMV to historical controls of pts receiving FM at the same dose and schedule without Vel. We also compared pts receiving FMV to all pts with MM treated with alloSCT including all regimens and donor types. The response criteria from the IMWG and M-Smart criteria were used to determine response and risk, respectively. Chi-square tests of association and Wilcoxon rank sum tests were performed to test for differences across groups. OS/PFS probabilities were calculated using the Kaplan-Meier product limit estimator with log rank-tests. Multivariate Cox proportional hazard models examined factors associated with OS/PFS. Results: Of the 54 pts who received FMV, 35 (65%) were male and the median age was 56 years. Twenty-seven pts had an HLA matched sibling donor and 27 had an unrelated donor. At the time of alloSCT, 5 pts were in a CR, 27 in a VGPR, 13 in a PR, 9 had < PR. Twenty eight pts (52%) had high risk disease. Twenty-nine pts (53%) received alloSCT as salvage, defined as relapsed or refractory to ASCT, and 25 pts (46%) as consolidation after ASCT. OS was 42% at 10 years. While 32 pts developed aGVHD, only 2 had ≥ Grade 3. Of the 31 pts who developed cGVHD, 23 were graded as extensive. TRM was 5% at day 100, and 15% over 10 years. Pts in the control groups had similar baseline characteristics to the FMV group. The only significant difference was 47 pts (72%) who received FM were transplanted as salvage, and 18 (28%) as consolidation after ASCT (p=0.035). The total number of pts who did not receive FMV (non FMV) was 121, with 66 pts receiving FM. Compared to pts who received FMV, there was no difference in OS for pts who received FM or the non FMV group, 35% (p=0.55) and 48% (p=0.855) respectively. There was no difference in pts who developed aGVHD, however 9 pts (13%) had ≥ grade 3 aGVHD in the FM group (p=0.004) and 15 (12%) in the non FMV group (p=0.006). The cumulative incidence of cGVHD was similar with 51% for pts receiving FM and 60% for FMV pts (p=0.32). TRM was similar to pts who had received FMV; 18% for FM and 17% for non FMV. There were no differences between the 3 groups across disease risk, donor type, or disease status at the time of alloSCT. Multivariate analysis of the 3 groups, shows achieving a CR after alloSCT (p=0.0006) or having cGVHD (p=0.0004) predicts for improved OS, while severe aGVHD (p=0.0002) predicts for decreased OS. Discussion: While FMV was associated with a lower incidence of severe aGVHD, the addition of bortezomib to the FM backbone did not improve PFS or OS. Day 100 TRM was low for all regimens, and the addition of Vel did not impact overall TRM. For all 175 pts, those who achieve a CR after alloSCT had a significantly improved OS. This prompts the question of whether strategies should be employed post alloSCT to maximize response to a CR, and the role of achieving MRD negativity after alloSCT also needs to be elucidated. Figure Figure. Disclosures Siegel: BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Biran:Amgen: Consultancy, Speakers Bureau; BMS: Research Funding; Merck: Research Funding; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Skarbnik:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Download Full-text

Multicenter Analysis of Treatment and Outcomes for Patient with TP53 Mutated AML in the Era of Novel Therapies; Significant Impact of Allogeneic Stem Cell Transplantation on Survival

Blood ◽

10.1182/blood-2021-147639 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 797-797

Author(s):

Talha Badar ◽

Mark R. Litzow ◽

Rory M. Shallis ◽

Jan Philipp Bewersdorf ◽

Antoine Saliba ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Research Funding ◽

Univariate Analysis ◽

Advisory Board ◽

Novel Therapies ◽

Advisory Committees ◽

Tp53 Mutations

Abstract Background: TP53 mutations occur in 10-20% of patients with AML, constitute high-risk disease as per ELN criteria, and confer poorer prognosis. Venetoclax combination therapies and CPX-351 were recently approved for AML treatment and lead to improved outcomes in subsets of high-risk AML, however the most effective approach for treatment of TP53-mutated (m) AML remains unclear. In this study we explored the clinical outcome of TP53m AML patients treated over the last 8 years as novel therapies have been introduced to our therapeutic armamentarium. Methods: We conducted a multicenter observational study in collaboration with 4 U.S. academic centers and analyzed clinical characteristics and outcome of 174 TP53m AML patients diagnosed between March 2013 and February 2021. Mutation analysis was performed on bone marrow specimens using 42, 49, 199, or 400 gene targeted next generation sequencing (NGS) panels. Patients with an initial diagnosis of AML were divided into 4 groups (GP) based on the progressive use of novel therapies in clinical trials and their approvals as AML induction therapy during different time periods: 2013-2017 (GP1, n= 37), 2018-2019 (GP2, n= 53), 2019-2020 (GP3, n= 48) and 2020-2021 (GP4, n= 36) to analyze difference in outcome. Results: Baseline characteristics were not significantly different across different GP, as shown in Table 1. Median age of patients was 68 (range [R], 18-83), 65 (R, 29-88), 69 (R, 37-90) and 70 (R, 51-97) years in GP1-4, respectively (p=0.40). The percentage of patients with de novo AML/secondary AML/therapy-related AML in GP1-4 was 40/40/20, 36/29/24, 37.5/37.5/25 and 28/52/20, respectively (p=0.82). The proportion of patients with complex cytogenetics (CG) was 92%, 89%, 96% and 94% in GP1-4, respectively (p=0.54). The median TP53m variant allele frequency (VAF) was 48% (range [R], 5-94), 42% (R, 5-91), 45% (R, 10-94) and 60% (R, 8-82) in GP1-4, respectively (p=0.38). Four (11%), 13 (24.5%), 10 (21%) and 9 (25%) patients had multiple TP53 mutations in GP1-4, respectively (p=0.33). The proportion of patients who received 3+7 (30%, 16%, 6% & 8%; p=0.01), HMA only (11%, 18%, 2% & 8%; p=0.06), venetoclax-based (2.5%, 12%, 48%, & 61%; p <0.01) and CPX-351 induction (16%, 40%, 28% & 5%; p<0.001) were varied in GP1-4, respectively. The rate of CR/CRi was 22%, 26%, 28% and 18% in GP1-4, respectively (p=0.63). Treatment related mortality during induction was observed in 3%, 7%, 10% and 17% of patients in GP1-4, respectively (p=0.18). Overall, 28 (16%) patients received allogeneic hematopoietic stem cell transplantation (alloHCT) after induction/consolidation: 22%, 15%, 17% and 11% in GP1-4, respectively (p=0.67). In subset analysis, there was no difference in the rate of CR/CRi with venetoclax-based regimens vs. others (39% vs 61%, p=0.18) or with CPX-351 vs. others (25% vs 75%, p=0.84). The median progression-free survival was 7.7, 7.0, 5.1 and 6.6 months in GP1-4, respectively (p=0.60, Fig 1A). The median overall survival (OS) was 9.4, 6.1, 4.0 and 8.0 months in GP1-4, respectively (p=0.29, Fig 1B). In univariate analysis for OS, achievement of CR/CRi (p<0.001) and alloHCT in CR1 (p<0.001) associated with favorable outcome, whereas complex CG (p=0.01) and primary refractory disease (p<0.001) associated with poor outcome. Multiple TP53 mutations (p=0.73), concurrent ASXL1m (p=0.86), extra-medullary disease (p=0.92), ≥ 3 non-TP53m mutations (p=0.72), TP53m VAF ≥ 40% vs. < 40% (p=0.25), induction with CPX-351 vs. others (p=0.59) or venetoclax-based regimen vs. others (p=0.14) did not show significance for favorable or poor OS in univariate analysis. In multivariable analysis, alloHCT in CR1 (hazard ratio [HR]=0.28, 95% CI: 0.15-0.53; p=0.001) retained an association with favorable OS and complex CG (HR 4.23, 95%CI: 1.79-10.0; p=0.001) retained an association with dismal OS. Conclusion: We present the largest experience with TP53m AML patients analyzed by NGS. Although outcomes were almost universally dismal, alloHCT appears to improve the long-term survival in a subset of these patients. Effective therapies are warranted to successfully bridge patients to alloHCT and to prolong survival for transplant ineligible patients. Figure 1 Figure 1. Disclosures Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Litzow: Omeros: Other: Advisory Board; Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Jazz: Other: Advisory Board; AbbVie: Research Funding; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Shallis: Curis: Divested equity in a private or publicly-traded company in the past 24 months. Goldberg: Celularity: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aprea: Research Funding; Arog: Research Funding; DAVA Oncology: Honoraria; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Prelude Therapeutics: Research Funding; Aptose: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Atallah: BMS: Honoraria, Speakers Bureau; Takeda: Consultancy, Research Funding; Amgen: Consultancy; Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Research Funding. Foran: revolution medicine: Honoraria; gamida: Honoraria; bms: Honoraria; pfizer: Honoraria; novartis: Honoraria; takeda: Research Funding; kura: Research Funding; h3bioscience: Research Funding; OncLive: Honoraria; servier: Honoraria; aptose: Research Funding; actinium: Research Funding; abbvie: Research Funding; trillium: Research Funding; sanofi aventis: Honoraria; certara: Honoraria; syros: Honoraria; taiho: Honoraria; boehringer ingelheim: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding.

Download Full-text

Outcome of Autologous Stem Cell Transplantation in Waldenström's Macroglobulinemia

Blood ◽

10.1182/blood-2018-99-116496 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2149-2149

Author(s):

Romil Patel ◽

Neeraj Y Saini ◽

Ankur Varma ◽

Omar Hasan ◽

Qaiser Bashir ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Advisory Committees ◽

First Remission ◽

Relapsed Disease

Abstract Introduction: The role of autologous hematopoietic stem cell transplantation (auto-HCT) in the management of patients with Waldenström Macroglobulinemia (WM), a rare, indolent lymphoma, has not been established. We had previously published our experience with auto-HCT in a small cohort of WM patients1. Here, we present an updated analysis of auto-HCT with a larger cohort of WM patients. Methods and study population: The study cohort was comprised of 29 patients who underwent high-dose chemotherapy and auto-HCT at MD Anderson Cancer Center (MDACC). The Kaplan-Meier method was used to create survival curves. Overall survival (OS) was defined as the duration from date of transplant to death or last date of follow-up in living patients. Progression-free survival (PFS) was defined as the duration from date of transplant to either progressive disease or death, whichever occurred first. Results: Median age at auto-HCT was 60 (range, 43-75 years). Eight patients (28%) had concurrent light chain amyloidosis (AL). Of the five patients who had MYD88 testing completed, 3 were positive for the MYD88 mutation. Additionally, of these 3 patients, 2 were also positive for CXCR4 mutation. Patients received a median of 2 lines (range 1-6) of therapy prior to auto-HCT; 3(10%) patients had primary refractory disease, 8(28%) were in first remission, and 18 (62%) had relapsed disease. Median time from transplant to last follow-up for the surviving patients was 5.3 years. Preparative regimens received by the patients were: Melphalan (n=20), BEAM-R (n=2), Busulfan/Melphalan (n=1), Cyclophosphomaide/Etoposide/total body irradiation (n=1), Thiotepa/Busulfan/Cyclophosphamide (n=1), and Carmustine/Thiotepa (n=1). Three patients further went on to receive allogeneic transplant either after relapse from auto-HCT or due to disease transformation to aggressive lymphoma. Twenty-eight patients achieved engraftment with a median time to neutrophil engraftment of 11 days (range, 10-15 days). One patient suffered primary graft failure due to progression of disease and died 84 days after transplant. Non-relapse mortality was 3.4% at 1 year. All patients were eligible for response evaluation. The median OS from diagnosis was 12.2 years. Overall response rate was 96%: complete response (n=8, 27.6%), very good partial response (n=5, 17.3%), partial response (n=15, 51.7%), and progressive disease (n=1, 3.4%). PFS and OS at 5 years were 43.3% and 62.9%, respectively. Median PFS and OS from auto-HCT were 4.1 and 7.3 years (Fig. 1A). The median OS from auto-HCT in first remission + primary refractory and relapsed disease was 8.2 years and 4.1 years, respectively.16 patients were alive at the time of censoring while 13 patients had died. Causes of death include relapsed disease (n=6), secondary malignancy (n=2), infection (n=1), chronic graft-versus-host disease (n=1), and unknown (n=3). 8 patients (28%) were positive for concurrent AL amyloidosis. The sites of amyloid involvement were kidneys (n=2), lungs (n=1), bone marrow (n=1), heart(n=1), lymph nodes(n=1), gastrointestinal tract (n=1) and subcutaneous fat aspirate(n=5). The median overall survival for patients with amyloid involvement (n=8) was 12 years. On univariate analyses, the number of chemotherapy regimens prior to transplant (≤ 2 vs >2 lines) was the strongest predictor of overall survival (p=0.03, HR 0.3, CI: 0.09-0.9, log-rank) and PFS (p=0.001, HR 0.24, CI: 0.07-0.85, log-rank). The median PFS in patients with ≤ 2 lines and > 2 lines of therapy was 71 months versus 19 months, respectively (Fig. 1B). Conclusion: Auto-HCT is safe and feasible in selected patients with WM, with a high response rate and durable remission even in patients with relapsed or refractory disease. References: Krina Patel et.al. Autologous Stem Cell Transplantation in Waldenstrom's Macroglobulinemia. Blood 2012 120:4533; Disclosures Thomas: Celgene: Research Funding; Bristol Myers Squibb Inc.: Research Funding; Acerta Pharma: Research Funding; Array Pharma: Research Funding; Amgen Inc: Research Funding. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Orlowski:Takeda: Consultancy; Celgene: Consultancy; Spectrum Pharma: Research Funding; Janssen: Consultancy; Kite Pharma: Consultancy; Sanofi-Aventis: Consultancy; BioTheryX: Research Funding; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Champlin:Otsuka: Research Funding; Sanofi: Research Funding. Patel:Poseida Therapeutics, Inc.: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Celgene: Research Funding.

Download Full-text