Influence of Donor Type (Sibling versus Matched Unrelated Donor versus Haploidentical Donor) on Outcomes after Clofarabine-Based Reduced-Intensity Conditioning Allograft for Myeloid Malignancies

Background: Allogeneic stem cell transplantation (alloSCT) offers cure chance for various hematologic malignancies, but graft- versus-host disease (GVHD) remains a major impediment. Anti-thymocyte globulin (ATG) is used for prophylactic T-cell depletion and GVHD prevention, but there are no clear guidelines for the optimal dosing of ATG. It is suspected that for patients with low absolute lymphocyte counts (ALCs), current weight-based dosing of ATG can be excessive, which can result in profound T-cell depletion and poor transplant outcome. Methods: The objective of the study is to evaluate the association of low preconditioning ALC with outcomes in patients undergoing matched unrelated donor (MUD) alloSCT with reduced-intensity conditioning (RIC) and ATG. We conducted a single-center retrospective longitudinal cohort study of acute leukemia and myelodysplastic syndrome patients over 18 years old undergoing alloSCT. In total, 64 patients were included and dichotomized into lower ALC and higher ALC groups with the cutoff of 500/μl on D-7. Results: Patients with preconditioning ALC <500/μl were associated with shorter overall survival (OS) and higher infectious mortality. The incidence of acute GVHD and moderate-severe chronic GVHD as well as relapse rates did not differ according to preconditioning ALC. In multivariate analyses, low preconditioning ALC was recognized as an independent adverse prognostic factor for OS. Conclusion: Patients with lower ALC are exposed to excessive dose of ATG, leading to profound T-cell depletion that results in higher infectious mortality and shorter OS. Our results call for the implementation of more creative dosing regimens for patients with low preconditioning ALC.

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Impact of Genomic Alterations on Outcomes in Myelofibrosis Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood.v128.22.2301.2301 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2301-2301 ◽

Cited By ~ 1

Author(s):

Raajit K. Rampal ◽

Roni Tamari ◽

Nan Zhang ◽

Caroline Jane McNamara ◽

Franck Rapaport ◽

...

Keyword(s):

Bone Marrow ◽

Research Funding ◽

Triple Negative ◽

Unrelated Donor ◽

Reduced Intensity Conditioning ◽

Hematopoietic Stem ◽

Disease Characteristics ◽

Donor Type ◽

The Impact ◽

Reduced Intensity

Abstract Introduction: The impact of genomic alterations, such as mutations in ASXL1, on the risk of disease progression and leukemic transformation in patients with myelofibrosis (MF) is well established. Further, emerging data suggests that the number and type of mutations may impact response to therapies such as ruxolitinib or imetelstat. Allogeneic hematopoietic stem cell transplant (allo-HSCT) remains the only potentially curative treatment for MF patients. However, the impact of somatic mutations on overall survival (OS) and relapse-free survival (RFS) is poorly understood. Using next-generation sequencing of pre-transplant blood and bone marrow samples from a well clinically-annotated cohort of MF patients who underwent allo-HSCT, we sought to determine the impact of mutational burden on outcomes. Methods: A multicenter retrospective analysis of a cohort of 84 patients was carried out. This included 52 patients treated on the MPD-RC 101 prospective study (NCT00572897), 18 patients treated at Prince Margaret Hospital, and 14 patients treated at Memorial Sloan Kettering Cancer Center. Patient and transplant characteristics are displayed in Table 1. DNA was extracted from pre-transplant bone marrow aspirate samples or peripheral blood samples. High-throughput sequencing of a panel of genes was performed. Average coverage of 829x (standard deviation of ±130) was obtained. Mutect was utilized to call single point variants (comparing our samples to a pool of normal samples) and PINDEL was used to call short insertions and deletions. We excluded all mutations present in at least one database of known non-somatic variants (DBSNP and 1000 genomes) and absent from COSMIC. Univariate Cox regression and Kaplan-Meier graphics were used to investigate the association of patient, transplant, and disease characteristics with OS and RFS. Results: JAK2V617F was the most frequent mutation detected in 41(48.8%) patients (Table 2). Eighteen patients (21.4%) had triple negative disease (negative for JAK2, MPL, and CALR mutations). Univariate analysis included the following: patient characteristics (age, gender), transplant characteristics (related vs. unrelated donor, matched vs. mismatched donor and myeloablative vs. reduced intensity conditioning) and disease characteristics (DIPSS and presence of mutations). Decreased OS was associated with unrelated donor status (HR 2.09, 95% CI: 1.03-4.23, p=0.04), reduced intensity conditioning (HR 4.21, 95% CI: 1.01-17.59, p=0.049), triple negative disease (HR 2.09, 95% CI: 1.02-4.30, p=0.04), and presence of U2AF1 (HR 2.53, 95% CI: 1.10-5.81, p=0.03) or SUZ12 mutations (HR 3.92, 95% CI: 1.19-12.21, p=0.02). Decreased RFS was associated with unrelated donor status (HR 2.27, 95% CI: 1.16-4.45, p=0.02), and the presence of SUZ12 mutation (HR 6.97, 95% CI: 2.37-20.49, p<0.001). A descriptive decrease in RFS in patients with U2AF1 (HR 2.15, 95% CI: 0.94-4.88, p=0.07) was observed but did not reach statistical significance. Importantly, mutations previously reported to be associated with reduced OS and RFS in the non-transplant setting, such as ASXL1, EZH2, IDH1/2, and SRSF2, were not associated with poorer outcomes in this analysis in transplanted patients. In an exploratory multivariate analysis including donor type (related vs. unrelated) and presence of U2AF1 and SUZ12 mutations, there was a significantly reduced OS and RFS in patients who harbor these mutations regardless of donor type (OS: HR 5.30, 95% CI: 2.08-13.47, p<0.001; RFS: HR 5.49, 95% CI: 2.27-13.30, p<0.001). In patients without the above mutations, having an unrelated donor was associated with worse OS (HR 2.55, 95% CI: 1.09-5.96, p=0.03) and RFS (HR 2.61, 95% CI: 1.17-5.83, p=0.02, Figure 1). Conclusions: Our analysis demonstrates that mutations previously associated with poor prognosis in MF, such as ASXL1, do not appear to confer a worsened prognosis in patients undergoing allo-HSCT, suggesting transplant may be able to overcome the impact of these mutations. However, mutations in SUZ12 and U2AF1 are associated with reduced OS in univariate and multivariate analysis (together with donor type). Further studies with larger cohorts of patients are indicated to validate these findings, and to elucidate the impact of these mutations on disease biology. Disclosures Rampal: Incye and CTI: Consultancy. Mascarenhas:Janssen: Research Funding; CTi Biopharma: Research Funding; Promedior: Research Funding; Merk: Research Funding; Incyte: Research Funding. Mesa:Galena: Consultancy; Gilead: Research Funding; Promedior: Research Funding; Incyte: Research Funding; CTI Biopharma: Research Funding; Celgene: Research Funding; Ariad: Consultancy; Novartis: Consultancy. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding.

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Post-transplant cyclophosphamide (PT-Cy) based haploidentical transplantation (haploHCT) versus matched sibling (MSD) or matched unrelated donor (MUD) reduced intensity conditioning (RIC) HCT for diffuse large b-cell lymphoma (DLBCL): A CIBMTR and EBMT analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.15_suppl.7056 ◽

2018 ◽

Vol 36 (15_suppl) ◽

pp. 7056-7056 ◽

Cited By ~ 1

Author(s):

Mehdi Hamadani ◽

Kwang Woo Ahn ◽

Carlos Litovich ◽

Finel Herve ◽

Sonali M. Smith ◽

...

Keyword(s):

Cell Lymphoma ◽

B Cell Lymphoma ◽

Unrelated Donor ◽

Reduced Intensity Conditioning ◽

Matched Unrelated Donor ◽

Haploidentical Transplantation ◽

Large B Cell Lymphoma ◽

Matched Sibling ◽

Large B Cell ◽

Reduced Intensity

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A Study of Factors Influencing Outcome In Patients with Haematological Malignancy Requiring High Dependency Support In a Large UK Haematology and Bone Marrow Transplant Centre

Blood ◽

10.1182/blood.v116.21.4732.4732 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4732-4732

Author(s):

Satarupa Choudhuri ◽

Tim Somervaille ◽

Phil Haji Michael ◽

Mike Dennis

Keyword(s):

Length Of Stay ◽

Haematological Malignancy ◽

Organ Support ◽

Unrelated Donor ◽

Reduced Intensity Conditioning ◽

Matched Unrelated Donor ◽

High Dependency ◽

Level 3 ◽

Full Intensity ◽

Reduced Intensity

Abstract Abstract 4732 Introduction: Controversy surrounds the decision to admit a patient with Haematological malignancy to receive treatment in a Level 2- High Dependency Unit with patients needing single organ support or Level 3 – intensive care with patents requiring two or more organ support setting. Little is known regarding factors influencing outcome of such patients when admitted to such a setting. Methodology: We performed a retrospective case note review supplemented by computer database analysis of all patients admitted to the High Dependency Unit (HDU) at Christie Hospital, Manchester between October 2008 and January 2010. Results: 53 episodes in 53 patients (Median age 60 (IQR 44–66) years; 36 (68%) male) with known haematological malignancy were studied. The underlying diagnoses included AML (40%), NHL/HCL (13%), CLL (11%), Multiple Myeloma (11%), ALL (9%) and CML (6%). 51% (27/53) had undergone Stem Cell Transplantation; 15% (8/53) Allogeneic from a Matched Unrelated Donor, 23% (12/53) Sibling and 13% (7/53) Autologous. Of the 20 Allogeneic transplants, 7 (35%) had Full Intensity and 11 (55%) had Reduced Intensity conditioning. 25% had Graft versus Host disease (GVHD) at the time of HDU admission. The trigger leading to HDU admission was septic shock (46%), bacterial pneumonia (24%), cardiac decompensation (10%) and other causes in 20% (viral pneumonia, infective colitis and neurological). Admission APACHE score in the overall cohort was 21 (IQR 17–25); 32% (17/53) required CPAP whilst 40% received inotropic support. Pre admission observations noted to be associated with subsequent increased mortality were tachycardia (heart rate>100), tachypnoea (respiratory rate > 20 per minute), systolic hypotension (SBP < 70mm Hg), acidaemia (pH < 7.4) and septic shock requiring ionotropic support. Of note is that neutropenia (absolute neutrophil count <1) at the time of HDU admission did not seem to affect outcome. In-hospital HDU mortality in the overall sample was 13% (7 of 53 patients) with median length of stay being 4 (IQR 2–7) days. 38% (20/53) were alive at 1 month and 31% (16/53) were still alive by 6 months post HDU discharge. 28% (15/53) were transferred from HDU for Level 3 support and all these patients were intubated and mechanically ventilated. Of these transfers, 40% (6/15) survived to discharge. Patients receiving Allogeneic Sibling donor transplants exhibited improved 1 and 6 month survival when compared to Allogeneic Matched Unrelated Donor transplant recepient (p=0.011) although no statistically significant difference in short and long term survival or in length of stay on HDU were noted between those who had received Full Intensity Conditioning compared to Reduced Intensity Conditioning. Using Kaplan-Meier Survival analysis, median survival in those with an underlying diagnosis of MDS/AML was 11 months compared to 3 months in NHL and CLL. Conclusion: Patients with Haematological conditions do not necessarily exhibit a uniformly poor outcome when admitted for Level 2 (High Dependency) care with 87% surviving the episode. This is further emphasized by the fact that 40% patients requiring intubation and invasive mechanical ventilation survived to discharge. Matched unrelated donor transplants fared worse compared to Sibling and Autologous transplant cases. Interestingly, patients receiving Full and Reduced Intensity conditioning regimes showed no difference in admission mortality and length of stay. Disclosures: No relevant conflicts of interest to declare.

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Reduced Intensity Conditioning Matched Unrelated Donor Allograft for Kostmann Syndrome.

Blood ◽

10.1182/blood.v106.11.3854.3854 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3854-3854

Author(s):

Jecko Thachil ◽

Barry Pizer ◽

Mark Caswell ◽

Russell Keenan

Keyword(s):

Effective Treatment ◽

Neutrophil Count ◽

Unrelated Donor ◽

Cell Transplant ◽

Reduced Intensity Conditioning ◽

Matched Unrelated Donor ◽

Post Transplant ◽

First Case ◽

Kostmann Syndrome ◽

Reduced Intensity

Abstract Kostmann syndrome is a congenital disorder of myelopoeisis characterized by an absolute neutropaenia and severe bacterial infections. The introduction of G-CSF has dramatically changed the prognosis of these patients in recent years; though in G-CSF refractory patients, haemopoeitic stem cell transplant is still the only effective treatment. We describe the first case report of a patient who, unresponsive to escalating doses of G-CSF, underwent reduced intensity conditioning, Matched Unrelated Donor (MUD) allograft and has been cured from this condition. A male child presented shortly after birth with infection of the umbilicus. He developed repeated infections in the first six weeks of his life including pneumonia and scrotal abscess. Investigations at this stage included a bone marrow examination, which confirmed a diagnosis of severe congenital neutropaenia and he was started on treatment with G-CSF at 5μg/kg/day. Since diagnosis, he had numerous episodes of ear and skin infections and recurrent abscesses, most often with Methicillin resistant Staphylococcus aureus (MRSA) that required repeated hospitalisations. As the patient did not have a matched related donor, dose escalations were tried with G-CSF at 14-day intervals though he did not respond to doses up to 160μg/kg/day. At this stage, we had a child who was not responding to G-CSF injections, had several infections and was a carrier of MRSA and also Vancomycin Resistant Enterococci, who did not have a matched sibling donor. It was decided then to proceed with a MUD transplant with a non-myeloablative prepatory regimen. The pre transplant conditioning included fludarabine 30mg/m2 from day −8 to day −5, CAMPATH-1H 0.2 mg/kg from day -6 to day −2 and thiotepa 250 mg/m2 from day −4 to −2. Ciclosporin was started from day −1 and GCSF (Lenograstim) at 5μg/kg from day +7. A total of 10.4×106 CD 34+ cells/kg recipient’s weight of stem cells was infused. The patient successfully engrafted with a neutrophil count greater than 0.5×109/L on day 12 with an unsupported platelet count reaching above 50×109/L on day 33. The post transplant period was complicated with grade II skin and gut GVH that responded well to increased doses of ciclosporin alone. Slight falls in neutrophil count were noted on days 28 and 113 after transplant, which resolved by adjusting ciclosporin dosage. He is now ten months post transplant and has not had any infections needing hospitalization and maintains his neutrophil count. Conclusion We have therefore demonstrated for the first time that reduced intensity conditioning transplant from a matched unrelated donor is a safe and effective treatment for uncomplicated Kostmann syndrome.

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