Allogeneic Hematopoietic Cell Transplantation and Cell Therapy

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Syed Ali Abutalib, MD

Syed Ali Abutalib, MD

Navneet Majhail, MD, MS

Navneet Majhail, MD, MS

As part of The ASCO Post’s continued coverage of the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition, here is an update on several studies of allogeneic hematopoietic cell transplantation (allo-HCT) and cellular therapy, as used in myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), and acute lymphoblastic leukemia (ALL).

ABSTRACT 703: Salvage treatment of MDS, secondary AML (with MDS-related changes), and CMML relapse after allo-HCT (excluding haploidentical transplantation and ≥ 2 human leukocyte antigen–mismatch recipients) with azacitidine, lenalidomide, and donor lymphocyte infusions (the AZALENA trial; N = 24)1

Regimen: Planned second interim safety analysis was performed with a daily dose of lenalidomide at 5 mg for 21 days of a 28-day cycle in combination with up to 8 cycles of azacitidine at 75 mg/m2/d on days 1 to 7, every 28 days, and donor lymphocyte infusions with 3 increasing T-cell dosages (0.5 × 106 to 1.5 × 107 cells/kg) given after cycles 4, 6, and 8.

Key Findings: Patients with molecular (54%) or hematologic (46%) relapses of MDS (58%), secondary AML (38%), or CMML (4%) after a median of 260 days (range = 61–2,659 days) following allo-HCT, were treated with a median of 5.5 cycles of lenalidomide per patient (range = 1–8; 83 cycles at 2.5 mg/d, 38 cycles at 5 mg/d). Concomitantly, patients received a median of 7 courses of azacitidine (range = 2–8), and 17 patients received at least 1 donor lymphocyte infusion (median = 2, range = 1–12). No dose-limiting toxicity was seen in the cohort of 10 patients treated with a lenalidomide dosage of 5 mg/d.

The [AZALENA trial] results suggest that the combination of azacitidine, lenalidomide, and donor lymphocyte infusions has promising clinical activity and can induce durable responses [in MDS, AML, and CMML].
— Syed Ali Abutalib, MD, and Navneet Majhail, MD, MS

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The overall response rate was 68% (complete response = 58%, partial response = 10%). Patients in complete remission remained in remission for a median of 183 days (range = 113–513 days). Four patients developed acute graft-vs-host disease, and 5 patients developed chronic graft-vs-host disease (moderate, n = 2; severe, n = 1). Grade 3 to 4 neutropenia (90%), thrombocytopenia (71%), and anemia (29%) occurred frequently, whereas nonhematologic adverse events greater than grade 2 were rare.

Clinical Implications: The results of the prospective -AZALENA trial show that an increase in the lenalidomide dosage to 5 mg/d (from 2.5 mg/d) is feasible, safe, and not associated with an excess incidence of graft-vs-host disease and toxicity. Furthermore, the results suggest that the combination of azacitidine, lenalidomide, and donor lymphocyte infusions has promising clinical activity and can induce durable responses. The trial -( identifier NCT02472691) is ongoing, with a goal of enrolling a total of 50 patients.2

ABSTRACT 1015: T-replete haploidentical cell transplantation using posttransplant cyclophosphamide for AML (n = 818), ALL (n = 286), and MDS (n = 221): retrospective analysis of the effect of transplant conditioning regimen intensity on outcomes3

Primary Endpoint: Disease-free survival

Patient Population: The median age of the study population was 54 years (18–70 years). Eighty percent of the patients with AML and ALL were in first or subsequent remission; 83% of patients with MDS had refractory anemia with excess blasts at the time of transplantation. Fifty-one percent of patients with AML and ALL had an intermediate Disease Risk Index score. In contrast, 50% of patients with MDS had a high or very high Disease Risk Index score.

Patients received myeloablative conditioning (n = 526) or reduced-intensity conditioning (n = 799) regimens and uniform graft-vs-host disease prophylaxis of posttransplant cyclophosphamide, calcineurin inhibitor, and mycophenolate mofetil. Approximately 50% of patients in the myeloablative conditioning and reduced-intensity conditioning groups had a hematopoietic cell transplantation–comorbidity index score of 0 to 2. Sixty-six percent of myeloablative conditioning recipients and 42% of reduced-intensity conditioning recipients received peripheral blood grafts. Among patients aged 18 to 54 years (n = 689), 55% received myeloablative conditioning and 54% received the reduced-intensity conditioning regimen. In patients aged 55 to 70 years (n = 636), 22% received myeloablative conditioning, and 78% received reduced-intensity conditioning.

Conditioning Regimens: Myeloablative conditioning primarily consisted of total-body irradiation plus fludarabine (33%) and busulfan with cyclophosphamide with or without fludarabine (36%). Other myeloablative conditioning regimens included total-body irradiation with cyclophosphamide or other agents (10%); fludarabine with 4 days of busulfan (13%); and melphalan at 140 mg/m2 plus fludarabine with or without thiotepa (9%).

Total-body irradiation at 200 cGy plus cyclophosphamide and fludarabine (84%) was the predominant reduced-intensity conditioning regimen. Other reduced-intensity conditioning regimens included total-body irradiation at 200 cGy plus busulfan or melphalan plus fludarabine (7%); fludarabine plus 2 days of busulfan (1%); and fludarabine plus melphalan at 100 mg/m2 with or without thiotepa at 5 mg/kg (8%).

Key Findings: Differences in transplant outcomes were observed between patients aged 18 to 54 years and those aged 55 to 70 years. In patients aged 18 to 54 years, who were equally likely to receive myeloablative conditioning or reduced-intensity conditioning, relapse risks were higher after the reduced-intensity conditioning regimen, which resulted in lower disease-free survival.

There were no differences in nonrelapse mortality or overall survival by conditioning regimen intensity. In patients aged 55 to 70 years, who were more likely to receive the reduced-intensity conditioning regimen, nonrelapse mortality was lower after reduced-intensity conditioning but without an advantage for relapse, disease-free, or overall survival. Consistent with the main analysis, a subset analysis limited to patients with AML also confirmed higher relapse rates (hazard ratio [HR] = 1.43, P = .03) and lower disease-free survival (HR = 1.38, P = .02) after reduced-intensity conditioning regimens in patients aged 18 to 54 years but not in patients aged 55 to 70 years.

Acute graft-vs-host disease (HR = 1.01, P = .94) and chronic graft-vs-host disease (HR = 0.82, P = .14) did not differ by the intensity of the conditioning regimen. The nonrelapse mortality risks were higher after reduced-intensity conditioning with non–total-body irradiation compared to reduced-intensity conditioning with the total-body irradiation regimen.

Clinical Implications: Among younger adults (aged 18–54 years) with AML, ALL, and MDS, disease-free survival is better in patients who can tolerate a myeloablative conditioning regimen compared with a reduced-intensity conditioning regimen. In older adults (aged 55–70 years), nonrelapse mortality is lower with a total-body irradiation–based reduced-intensity conditioning regimen compared to a non–total-body irradiation reduced-intensity conditioning regimen. For patients who were deemed unsuitable for the myeloablative conditioning regimen, irrespective of age, total-body irradiation at 200 cGy with cyclophosphamide and fludarabine is preferred over fludarabine plus melphalan with non–total-body irradiation with or without thiotepa.

ABSTRACT 813: Pre-engraftment gut colonization with Enterococcus casseliflavus after allo-HCT4

Methods: Allo-HCT recipients (n = 873) who had at least 1 positive rectal swab or stool culture for intrinsically vancomycin-resistant enterococci (Enterococcusgallinarum [n = 43] or Enterococcuscasseliflavus [n = 23]) between days –14 and +14 were analyzed. New admissions for allo-HCT were screened for vancomycin-resistant enterococci colonization in the gut weekly until discharge. A vancomycin-resistant enterococci chromogenic agar medium was used for species-level identification.

Key Findings: With a median follow-up of 30 months, overall survival was significantly better in patients (children and adults) with E casseliflavus (91% vs 62% at 3 years, P = .04), due to lower nonrelapse mortality (0% vs 18% at 3 years, P = .05). Two patients with E casseliflavus died within 3 years posttransplant, both due to relapsed disease. In contrast, 14 patients with E gallinarum died within 3 years posttransplant: 7 patients due to relapse and 7 from other causes (4 with graft-vs-host disease, 1 with infection, 1 with graft failure, and 1 with sinusoidal obstructive syndrome).

In multivariable analysis, E casseliflavus gut colonization was associated significantly with reduced all-cause mortality (HR = 0.20, 95% confidence interval [CI] = 0.04–0.91; P = .04). No significant differences were seen between the groups in 180-day acute (grades 2–4) graft-vs-host disease (P = .19), 1-year chronic graft-vs-host disease (P = .56), 100-day bacteremia (P = .59), or day +100, Clostridium difficile infection (P = .79).

Clinical Implications: In this single-center retrospective analysis, pre-engraftment gut colonization with Enterococcuscasseliflavus (but not Egallinarum) improved survival after allo-HCT. Future mechanistic studies of the interactions between E casseliflavus and the transplant host can probably guide the development of novel microbiota-oriented therapeutics. It is important to note that although positive and negative associations between the microbiota composition and host health have been widely reported, the mechanisms whereby the microbiota affects host health remain incompletely understood.5

ABSTRACT 200: Thrombopoietin receptor agonists (eltrombopag and romiplostim) for thrombocytopenia after allo-HCT6

Primary Endpoint: Platelet count ≥ 50,000/μL

Definitions: Prolonged isolated thrombocytopenia (n = 16) was defined as the engraftment of all blood cell lines except platelet count, which remained ≤ 20,000/μL for 7 consecutive days, or requirement of platelet transfusion for more than 60 days after allo-HCT. Secondary failure of platelet recovery (n = 71) was defined as a decline of platelet counts to ≤ 20,000/μL for 7 consecutive days or requirement of transfusion after achievement of a platelet count ≥ 50,000/μL without transfusion for 7 days.

Sorafenib maintenance therapy after allo-HCT significantly reduced the risk of relapse or death in patients with FLT3-ITD–positive AML. However, this was a small trial that was terminated prematurely due to poor accrual.
— Syed Ali Abutalib, MD, and Navneet Majhail, MD, MS

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Key Findings: Median platelet count before thrombopoietin receptor agonist therapy was 14,000/μL (1,000–57,000/μL). Platelet recovery to ≥ 50,000/μL was achieved in 60%, and the response occurred at a median of 56 days (2– 47 days). Responses were similar, considering all potential causes of thrombocytopenia evaluated. Patients with a decreased number of megakaryocytes prior to treatment (81%) showed a worse response to therapy (median time to ≥ 20,000/μL platelets was 43 days in this group vs 28 days among patients with normal megakaryocyte levels; P = .011) and a lower rate of platelet recovery to ≥ 50,000/μL (62% with low megakaryocyte levels vs 85% with normal megakaryocyte levels).

The median treatment duration was 62 days (7–700 days), and 62% of patients discontinued thrombopoietin receptor agonists and maintained a response subsequently. Grade 3 to 4 adverse events (ie, hepatic effects and asthenia) were observed in 2% of the patients. At last follow-up (median = 10 months, range = 1–59 months), 72% of the patients maintained the response, and 61 patients were alive. The death rate was significantly lower in responders than nonresponders to thrombopoietin receptor agonists—15% vs 53% (P < .001), respectively.

Clinical Implications: The results of this retrospective multicenter study are encouraging and support further exploration of thrombopoietin receptor agonists in the allo-HCT setting.

ABSTRACT 661: Sorafenib as maintenance therapy after allo-HCT in patients with FLT3–internal tandem duplication (ITD)–positive AML: the randomized, double-blind, placebo-controlled, multicenter SORMAIN trial7

Primary Endpoint: Relapse-free survival, defined as hematologic relapse or death from any cause

Key Findings: The median age was 54 years (interquartile range = 47.75–61.33 years) for the entire study population and not significantly different between the sorafenib (n = 43) and placebo (n = 40) groups. With a median follow-up of 41.8 months after randomization (interquartile range = 24.1–42.5 months), median relapse-free survival was 30.9 months (lower bound of 95% CI = 5.2 months) in the placebo group vs not reached in the sorafenib group, corresponding to a 2-year relapse-free survival of 53.3% (95% CI = 36.5%–67.5%) in the placebo vs 85.0% (69.5%–93.0%) in the sorafenib group (HR = 0.39, 95% CI = 0.18–0.85; P = .0135).

Overall, sorafenib was well tolerated. The most common grade 3 to 4 adverse event in both groups was acute graft-vs-host disease (occurring in 7 patients in the placebo group vs 9 in the sorafenib group).

Clinical Implications: Sorafenib maintenance therapy after allo-HCT significantly reduced the risk of relapse or death in patients with FLT3-ITD–positive AML. However, this was a small trial that was terminated prematurely due to poor accrual. Larger ongoing trials using second-generation FLT3 inhibitors (eg, BMT CTN 1506) will address this question. Also, see abstract 708 from the ASH Annual Meeting & Exposition for another report on outcomes with sorafenib after allo-HCT.

Dr. Abutalib is Associate Director, Hematology and BMT Program; Director, Clinical Apheresis Program, Cancer Treatment Centers of America, Zion, Illinois; Associate Professor, Roseland Franklin University of Medicine and Science; as well as Founder and Co-Editor, Advances in Cell and Gene Therapy. Dr. Majhail is Professor, Cleveland Clinic Lerner College of Medicine; Director, Blood & Marrow Transplant Program, Cleveland Clinic; and President, American Society of Transplantation and Cellular Therapy (previously American Society for Blood and Marrow Transplantation). 

DISCLOSURE: Dr. Abutalib is an advisor for AstraZeneca and Takeda Inc. Dr. Majhail has received honoraria from Atara Biotherapeutics and Incyte, is a consultant/advisor with Anthem, Inc, has received travel/accommodations/expenses from Atara Biotherapeutics and Incyte.


1. Schroeder TM, et al: Treatment of MDS, AML and CMML relapse after allogeneic blood stem cell transplantation with azacitidine, lenalidomide and donor lymphocyte infusions: Results from the second interim analysis of the prospective AZALENA trial (NCT02472691). 2018 ASH Annual Meeting & Exposition. Abstract 703. Presented December 3, 2018.

2. Azacitidine, lenalidomide and DLI as salvage therapy for MDS, CMML and sAML relapsing after allo-HSCT (AZALENA). Available at Accessed March 19, 2019.

3. Solomon SR, et al: T-replete haploidentical cell transplantation using post-transplant cyclophosphamide for acute myeloid leukemia, acute lymphoblastic leukemia and myelodysplastic syndrome: Effect of transplant conditioning regimen intensity on outcomes. 2018 ASH Annual Meeting & Exposition. Abstract 1015. Presented December 3, 2018.

4. Rashidi A, et al: Pre-engraftment gut colonization with enterococcus casseliflavus improves survival after allogeneic hematopoietic cell transplantation. 2018 ASH Annual Meeting & Exposition. Abstract 813. Presented December 3, 2018.

5. Whangbo J, et al:. Antibiotic-mediated modification of the intestinal microbiome in allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 52:183-190, 2017.

6. Bento L, et al: Thrombopoietin receptor agonists for severe thrombocytopenia after allogeneic stem cell transplantation: Experience of a multicenter study from the Grupo Español De Trasplante Hematopoyético (GETH). 2018 ASH Annual Meeting & Exposition. Abstract 200. Presented December 1, 2018.

7. Burchert A, et al: Sorafenib as maintenance therapy post allogeneic stem cell transplantation for FLT3-ITD positive AML: Results from the randomized, double-blind, placebo-controlled multicentre SORMAIN trial. 2018 ASH Annual Meeting & Exposition. Abstract 661. Presented December 3, 2018.

8. Bazarbachi A, et al: Post-transplant sorafenib improves overall survival in FLT3 mutated AML: A report from the EBMT Acute Leukemia Working Party. 2018 ASH Annual Meeting & Exposition. Abstract 708. Presented December 3, 2018.