Search

Sirolimus, tacrolimus and antithymocyte globulin as GVHD prophylaxis in HLA-mismatched unrelated donor hematopoietic cell transplantation: a single institution experience

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative approach in patients with multiple myeloma, but its use for consolidation of first remission has not yet been fully explored. Twenty-two myeloma patients with very good partial response (VGPR) or CR received allogeneic peripheral blood grafts as consolidation from HLA-matched donors between 2007 and 2012. Conditioning regimens were fludarabine (30 mg/m(2) i.v. if with bortezomib and 40 mg/m(2) i.v. when without bortezomib, × 4 days) plus melphalan (70 mg/m(2) intravenously × 2 days) with (n=13) or without (n=9) bortezomib (1.3 mg/m(2)). The cumulative incidence of grades II - IV acute GVHD at day 100 was 45% (95% CI: 24-65%) and moderate-to-severe chronic GVHD at 2 years was 46% (95% CI: 19-69%). With a median follow-up of 18 (range, 2-61) months, the 2-year PFS estimate is 74.8% (95% CI: 45-90%), which compares favorably with the 52% (95% CI: 35-66%) after autologous HCT for similar patients (a median follow-up of 30 (range, 9-55) months). We are conducting a phase 2 study to assess the efficacy of allogeneic HCT as post-remission therapy.

Allogeneic hematopoietic cell transplantation offers improved survival in patients with ALL, but with regimens containing TBI, the nonrelapse mortality is 20-40%. Efforts to lessen transplant toxicities by reducing conditioning regimen intensity have led to increased relapse risk. Therefore, there is a need for less toxic regimens that maintain an anti-leukemia effect. We report here a retrospective review of 65 patients with ALL in first remission receiving grafts from allogeneic donors after fludarabine 40 mg/m(2)/day for 4 days and i.v. BU targeted to a median daily area under the concentration-time curve below 6000 μmoles min/L. At 2 years after transplantation, OS was 65% (95% confidence interval (CI): 52-77%), relapse-free survival was 61% (95% CI: 48-73%), cumulative incidence of relapse was 26% (95% CI: 17-39%) and cumulative incidence of nonrelapse mortality was 14% (95% CI: 8-26%). Age over 35 years, Ph chromosome positivity and minimal residual disease at transplant did not adversely affect outcomes. Pharmacokinetically targeted BU and fludarabine can provide intensive pre-transplant conditioning for adults with ALL in first remission, with promising relapse-free and OS rates.

s / Biol Blood Marrow Transplant 21 (2015) S322eS354 S344 Teresa Field , Linda Kelley , Mohamed Kharfan-Dabaja , Frederick L. Locke , Asmita Mishra , Michael L. Nieder , Taiga Nishihori , Jose-Leonel Ochoa-Bayona , Lia Elena Perez , Marcie L. Riches , Claudio Anasetti . 1 Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; 2 Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL Standard primary therapy for chronic graft vs. host disease (GVHD) is incompletely effective. Based on biologic insights implicating pathogenic B cells, we conducted a phase I-II trial examining the combination of standard ( 1mg/kg/day prednisone) glucocorticoid therapy with ofatumumab, a humanized anti-CD20 monoclonal antibody, for primary chronic GVHD therapy (NCT01680965). We here report the results of the phase I trial. Patients age 18 with NIH Consensus moderate-severe chronic GVHD newly requiring 1mg/kg/day prednisone were treated at three escalating dose levels (300mg, 700mg, and 1,000mg) of IV ofatumumab on day 1 and 14 of initial glucocorticoid therapy. Dose-limiting toxicity (DLT) was defined by the following: grade 4 infusion reactions, related grade 4 constitutional symptoms, related grade 3 organ toxicities, and grade 4 neutropenia lasting >14 days. Secondary endpoints included: adverse events, infectious complications, clinical response to therapy including reduction in prednisone dose, and serial measures of lymphocyte subsets and immunoglobulins. A total of 12 patients (median age 54, range 25-72) were treated (dose level 1: n1⁄43; level 2: n1⁄43; level 3: n1⁄46). At enrollment, overall chronic GVHD was moderate (n1⁄47) or severe (n1⁄45), with diverse organ involvement (skin: n1⁄48; mouth: n1⁄48; eye: n1⁄48; lung: n1⁄44; GI: n1⁄43; liver: n1⁄45; genital: n1⁄42; joint/fascia: n1⁄45), and both overlap (n1⁄47) and classic (n1⁄45) sub-types were represented. KPS was 80% in 11/12, median platelet count was 164 (range 92287), and median bilirubin 0.6 (range 0.2-0.9). Infusion of ofatumumab was well tolerated: Two infusion reactions (grades 2 and 3) occurred, resolved with supportive care, and all patients completed d1 and 14 infusions. No DLT was observed. From the total number of adverse events (n1⁄427), possibly related AE (n1⁄43) included grade 1 fatigue, grade 1 transaminitis, and grade 3 hand/foot cramping. Infectious complications were expected, and there were no cases of hepatitis B reactivation or progressive multifocal leukoencephalopathy (PML). At 3 months after therapy initiation, overall clinical response among evaluable patients was CR (n1⁄41), PR (n1⁄47), or SD (n1⁄41), and responses were sustained at 6 months (including one conversion from PR to CR). Encouraging reduction in prednisone dose was observed at 3 (median 89%, range 57-100%) and 6 months (median 93%, range 71-100%). Therapy produced significant B-lymphopenia (figure). Ofatumumab in combination with prednisone is safe, and phase II examination of efficacy is ongoing.

Abstract 1333 In a prior retrospective analysis, we reported no adverse effects of pre-transplant 5-azacitidine on subsequent allogeneic hematopoietic cell transplantation (HCT) outcomes. We now report the results of a prospective observational clinical trial with the objective of evaluating HCT outcomes following pre-HCT therapy with 5-azacitidine. Twenty-three patients seen in consultation for HCT and medically eligible for a donor search were enrolled and received 5-azacitidine [75mg/m2 for 7 days every 4 weeks] until a suitable donor was identified. Four did not proceed to transplant for the following reasons: failure to obtain insurance approval due to patient age, failure of the pre-HCT organ evaluation although a donor was identified, CNS hemorrhage in setting of chronic anti-coagulation five days prior to HCT admission and one (62 years) declined HCT as only a HLA-A mismatched donor was available. Nineteen patients received a HCT following a myeloablative targeted busulfan fludarabine regimen. Median age at HCT was 57 years (25 – 67), 18 patients were older than 45 years, 7 older than 60 years. Disease at diagnosis was RCMD (3), RAEB2 (11), RAEB1 (3), CMML1 (1) and AMLM6 (1). IPSS at diagnosis was Int-1 (2), Int2 (9) and high (5), CMML1 (1), AMLM6 (1) and not evaluable (NE) (1). Cytogenetic risk was good (7), intermediate (5) and poor (7). Three patients had therapy related MDS. Patients received a median of 4 (1-6) cycles of 5-azacitidine. Median time from diagnosis (or time of progression and start of therapy in 2 patients) to HCT infusion was 195 days (107 – 350). Response to 5-azacitidine prior to HCT by the International Working Group 2006 criteria included partial response (8), stable disease (9) and 2 progressed. Two received leukemic induction chemotherapy prior to HCT. Disease status prior to HCT was RCMD (8), RAEB2 (2), RAEB1 (6), CMML1 (2) and AMLM6 (1). IPSS score prior to HCT was Low (1) Int-1 (6), Int2 (9) and poor (1) and CMML1 (2). Source of donor cells was peripheral blood siblings (7), matched unrelated donors (10) and mismatch unrelated donors (2). Median follow-up from HCT is 440 days (83-696). There are 3 patients who did not achieve remission (1) or relapsed (2) and 1 of the three remains alive with active disease. There are 3 non-relapse deaths, 2 due to infection and 1 due to GVHD. All deaths occurred between days 180 – 262. At one year OS is 69% (SE 0.12) and DFS is 63% (SE 0.12). In conclusion, pre-HCT 5-azacitidine was well tolerated, provided control of disease as a bridge to HCT and did not impose additional toxicity after allogeneic HCT with a promising 1 year progression-free survival. Controlled trials are needed to determine whether post-transplant relapse and survival are improved by pre-transplant 5-azacitidine. Disclosures: Field: Celgene: Research Funding. Perkins:Celgene: Research Funding. Komrokji:Celgene: Research Funding, Speakers Bureau. Lancet:Celgene: Research Funding. Alsina:Celgene: Research Funding. List:Celgene: Research Funding. Anasetti:Celgene: Research Funding.

Abstract 3054 Background: We previously reported the interim results of a phase II trial of PLD, low dose DEX and LEN in patients with NDMM. After a median of 4 cycles, the overall response rate (ORR) was 71% with 50% of patients achieving VGPR or better (ASCO 2009 Ann Meeting Proc #8518). However, due to a high rate of grade 3/4 fatigue and neutropenia, a dose reduction in PLD was recommended in order to improve tolerance and avoid treatment interruption. We herein report the updated results of this combination. Methods: The first 29 patients received PLD (40 mg/m2 on day 1), DEX (40 mg on days 1–4) and LEN (25 mg Days 1–21) every 28 days (for 2 cycles beyond best response). Prophylactic low dose aspirin, acyclovir and fluoroquinolone were recommended. Patients not eligible or not wishing to proceed with high-dose therapy continued on the tolerated dose of LEN and DEX until disease progression or unacceptable toxicity. PLD was reduced to 30 mg/m2 after the first 29 patients as described in background section. Results: Between 2/2008 and 7/2010, 47 of a planned 60 patients were enrolled. 3 patients were screen failures and are not included in subsequent analysis. The mean age was 63 years (36-78) and 53% were males. The median β2microglobulin was 2.8 mg/dL (21% had β2m>3.5). Using the IMWG criteria and after a median of 6 cycles of therapy, 5 patients had CR or sCR, 15 patients had VGPR, 14 patients had a PR, 6 patients had SD, 1 patient had PD, 3 patients were not evaluable (failure to complete 1 cycle of therapy for reasons other than PD). The overall response rate was 83% with 49% VGPR and better. For the cohort of patients treated after the dose reduction of PLD, the ORR was 88%, and VGPR and better was noted in 50%. In the patients treated with the reduced dose of PLD, no grade 4 toxicities were noted and the following grade 3 toxicities were noted: neutropenia (25%), fatigue (12.5%), infections (18%, only 1 patient had febrile neutropenia). No grade 3 or 4 venous thromboembolic events, anemia and thrombocytopenia were noted. This compares favorably with 48%, 10%, 7%, 21%, and 20% grade 3/4 neutropenia, anemia, thrombocytopenia, fatigue and infections, respectively, in the 29 patients treated at the higher dose of PLD. 18 patients proceeded to high-dose therapy (median CD34+ 4.24×106, 8 patients had stem cell collection with GCSF alone, 8 with AMD3100, 2 with cyclophosphamide). 9 patients received maintenance therapy with lenalidomide and dexamethasone. Survival and progression free results remain immature. Conclusion: The combination of PLD, LEN and DEX is an active regimen in patients with NDMM. The dose reduction of PLD in this regimen resulted in better tolerance without a compromise in efficacy due to less frequent treatment interruptions. Disclosures: Baz: celgene: Consultancy, Research Funding; millenium: Research Funding; orthobiotec: Research Funding. Off Label Use: use of pegylated liposomal doxorubicin and lenalidomide in newly diagnosed myeloma rather than in relapsed or refractory myeloma. Hussein:celgene: Employment. Sullivan:Merck: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Merrion: Membership on an entity's Board of Directors or advisory committees. Alsina:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Ortho Biotech: Research Funding.

Abstract 4756 Background: Considerable advances in the treatment of myeloma patients have culminated in the approval of novel agents (thalidomide, bortezomib, lenalidomide) with survival benefits noted for each. The outcomes of patients younger than 65 years have been shown to be improved with the availability of novel therapies. However, older adults, who comprise the majority of patients with myeloma, have not experienced the same improvement in outcomes as noted in epidemiologic studies (Brenner et al. Hematologica 2009. 94(2): 270 and Schaapveld et al, Eur J Cancer. 2009. 46(1):160.). We postulated that lack of access to novel agents, difference in disease biology, or competing causes of mortality might explain this finding. Method: We conducted a retrospective review of electronic medical records for patients 75 years of age or older at the time of diagnosis with symptomatic myeloma after 2004 (to allow for the availability of novel agents). Demographic information including comorbid conditions, disease characteristics (including risk features and cytogenetics), treatment information as well as survival data was collected. Risk stratification (standard or high risk) was based on the Mayo criteria (Steward et al. Leukemia 2007; 21: 529). Result: 72 patients (median age 78 years, range 75–89, 58% were older than 80 years) with symptomatic myeloma were the subjects of this study. Seventy-two percent were males and 28%, 15%, 60% and 29% had a history of cardiac dysfunction (defined as CAD or CHF), diabetes, hypertension and another malignancy (excluding non melanoma skin cancer) respectively. While 31 patients had missing information to determine the International Staging System; 29%, 32% and 39% had ISS stages 1, 2, and 3, respectively (similar to what is expected in younger cohorts). Moreover, using the Mayo risk model, 31% of patients had high risk disease. The median number of systemic therapies received was 2 (range 0–6). First line therapy did not include a novel agent in 29% of patients (who received alkylating agents 12%, anthracyclines 4%, corticosteroids alone 13%) and at the time of relapse, all but 4 patients had received a novel agent. First line therapy consisted of lenalidomide based regimens (30%), bortezomib based regimens (12%), thalidomide based regimens (28%) and a combination of novel agents (1%). The median overall survival for the entire cohort was 46 months (95% CI: 36.4–56.2 months). Conclusion: Older adults (greater than 75 years of age) with multiple myeloma continue to experience a shortened survival despite the use of novel agents and without a discernable higher incidence of high risk disease suggesting competing causes of mortality and tolerance to therapy may significantly limit the benefit of novel therapies in this age group. To address these limitations, we have initiated a clinical trial evaluating a sequential response adapted lenalidomide based therapy for older adults with newly diagnosed myeloma in order to minimize treatment related toxicities. Disclosures: Alsina: Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Ortho Biotech: Research Funding. Baz:celgene: Consultancy, Research Funding; millenium: Research Funding; orthobiotec: Research Funding.

Abstract 2381 Allogeneic hematopoietic cell transplantation (HCT) remains the only curative treatment strategy for patients with Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML). Recent reduction of the transplant related toxicity has permitted the expansion of empiric age limitations for HCT up to 75 years. There has been limited comparative data on HCT focusing on donor availability in patients with MDS/CMML. Between January 2004 and September 2009, a total of 255 new patients (NP) with a diagnosis of MDS or CMML were evaluated for HCT at Moffitt Cancer Center. This report describes the outcomes of these patients with emphasis on donor availability. Donor Search Results: Of the 255 NP, 58 did not undergo a donor search. Reasons for not proceeding were as follows: Medicare declined coverage due to age >65 (18), waiting as have low risk disease (15), patient declined (6), patient seen as second opinion only (7) and patient was not eligible for HCT (12). These patients were not included in the survival analysis. Of the 197 patients who had a donor search initiated, a sibling (SIB) matched unrelated (MUD) or single HLA antigen/allele mismatch (mMUD) unrelated adult donor was found in 173 patients. A suitable adult donor was not identified in the remaining 24 patients. To mitigate bias due to factors giving a survival advantage to patients who were stable enough to survive the donor and proceed to HCT, the survival analysis included only those patients alive 90 days after the donor search was initiated. We have been able to identify donors within this time frame for 99% of the patients who ever found one, although time to transplant is longer. At the 90 days landmark, there were 164 patient in the Donor cohort, and 19 patients in the No Donor cohort. Donor Cohort: The median age was 56.6 yrs (18.5 – 73.5). Ninety-seven patients (59%) were older than 55 yrs and 26 (16%) were above 65 yrs. At the time of the transplant consult, IPSS risk was Low (10), Int-1 (44), Int-2 (48), High (25), AML (21), CMML (13), or not evaluable (NE) (3). Donors included SIB (60), MUD (75) and mMUD (29). Median follow-up of surviving patients is 27.7months (7.2 – 70.7). No Donor Cohort: Median age was 57.4 yrs (32.6 – 68.1) with 12 patients (63%) older than 55 yrs and 3 (16%) patients older than 65 years of age. IPSS at initiation of the donor search was Int-1 (5), Int-2 (6), High (5), AML (1) and CMML (2). Median follow-up is 9.2 months (1.4 – 61.5). Of the 19 patients with no donor, 3 patients received an umbilical cord blood HCT elsewhere and were analyzed by intent to treat. Outcomes: Patients with a donor had significantly improved overall survival from time of donor search vs. patients with no donor (P=0.007) with 2 year OS of 48% vs. 23%, respectively. Median survival for the donor group was 22.2 months [95% CI 14.7 – 35.7] vs. 10.1 months for those without a donor [95% CI 2.3 – 14.7]. Transplant: Of the 164 patients with a donor, 121 (74%) patients received the planned allogenic transplants. The 2-year overall survival (OS) after transplantation is similar for SIB (51%), MUD (39%) or mMUD (68%) transplant recipients (P=0.4), and also similar by age below or above 55 years (P=0.7). These data demonstrate that most patients with MDS or CMML can have a suitable donor identified and proceed to HCT. Overall survival is significantly improved for those patients who have a suitable sibling or unrelated donor. Disclosures: Lancet: Eisai: Consultancy; Celgene: Honoraria. Alsina: Millenium: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy. List: Celgene: Research Funding.