Bone marrow failure syndromes are a heterogeneous group of diseases. With the major advancements in diagnostic tools and sequencing techniques, these diseases may be better classified and therapies may be further tailored. Androgens, a historic group of drugs, were found to stimulate hematopoiesis by enhancing the responsiveness of progenitors. These agents have been used for decades to treat different forms of bone marrow failure. With the availability of more effective pathways to treat BMF, androgens are less used currently. Nevertheless, this group of drugs may serve BMF patients where standard therapy is contraindicated or not available. In this article, we review the published literature addressing the use of androgens in BMF patients and we make recommendations on how to best use this class of drugs within the current therapeutic landscape.
Background A significant proportion of patients with acute myeloid leukemia (AML) will either be refractory to initial chemotherapy or will suffer refractory relapse. The role of allogeneic transplantation (SCT) in active disease is contentious. There is a growing body of literature that sequential chemotherapy, pioneered by the German FLAMSA regimen, followed by RIC SCT is a safe and efficacious modality in these patients, and there have been numerous modifications of this regimen, especially as amsacrineis not widely available. Fludarabine, cytarabineand and etoposide (VP16) (FLAV) have been reported as an effective salvage regimen. Here we report on single center outcomes of a variation of the FLAMSA regimen, substituting amsacrine for etoposide with mainly myeloablative conditioning. Methods Patients were offered this regimen if fit for allogenic HSCT and had AML which is refractory to two cycles of chemotherapy or refractory to one cycle and considered at high risk for complication with second cycles. Patients with MDS received this regimens if eligible for transplant with high or very high risk cytogenetics. All patients received cytoreductive chemotherapy consisted of fludarabine 30mg/m2/day x 4 days, Cytarabine 2g/m2/day x 4 days, etoposide 100mg/m2/day x 3days, commenced simultaneously. After 3 days of rest, conditioning chemotherapy consisted of fludarabine 30mg/m2 x 2 days and and IV busulfan 0.8mg/m2 q 6 hours; the number of busulfan doses varied between 8 - 12, depending on patient comorbidity. All patients received 2 doses of ATG at 2.5mg/m2/day on day -3 and -2. All patients received GCSF mobilized peripheral blood hematopoietic cells. Post-transplant GVHD prophylaxis consist of CsA and MMF. CsA was tapered from day+60 and stopped at day +90 in the absence of GVHD. MMF was discontinued between day +30 and day +40. Donor lymphocyte infusions were collected for planned prophylactic DLI. Results Twenty six patients received FLAV-SCT between March 2014 and July 2019. The median age was 38 (14-60); 16 (62%) female. Overall 12 (46%) pts had de novo AML, 10 (39%) pts had secondary or therapy related AML and 4 (15%) pts had MDS. Fourteen (54%) pts had adverse risk cytogenetics include 8 (31%) pts had complex or monosomal karyotype. Patients' characteristics are summarized in Table 1. All patients had active disease prior to FLAV-SCT. The median time for ANC and platelet engraftment was 14 (10 - 42) days and 17 (10 - 52) days respectively. Day 30 assessment shows CR in 16 (61%) pts and CR/CRi in 17 (65%) pts. Outcomes are summarized in Table 2. Three patients (12%) developed veno-occlusive disease. Acute GVHD grade II-IV and III-IV occurred in 9 (35%) pts and 2 (8%) pts respectively. Three (12%) patients developed chronic GVHD. Cumulative incidence of NRM at 100 days and 2 years was 8% and 12% respectively. The median OS for all pts was 5.2 months with 2 years rate of 32% (15 - 50). Among responders, the median OS and RFS were 19.2 months and 8.7 months, 2y-OS and RFS were 47% and 25%, respectively (Figure 1). Conclusion Our result demonstrates that transplant is an effective therapeutic modality in this very high risk refractory AML/MDS patients. Sequential chemotherapy (FLAV) followed by SCT with busulfan at myeloablative dose is tolerable with an acceptable toxicities and encouraging results. Figure 1 Figure 1. Disclosures Chaudhri: Novartis: Honoraria; Abbvie: Honoraria; Astra Zeneca: Honoraria. Alzahrani: King Faisal Specialist Hospital and Research Centre: Current Employment; Novartis: Consultancy, Honoraria; Bayer: Consultancy, Honoraria, Speakers Bureau; Sobi: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau.
e19057 Background: Haplo-HCT is a potentially curative intervention for hematological malignancies. A number of transplant platforms are used by different groups. We adopted a myeloablative conditioning (MAC) protocol, BM graft with post-transplant cyclophosphamide (PTCy) for GvHD prophylaxis as our program cares for young patients with hematologic malignancies. High grades GvHD were noticed, antithymocyte globulin (ATG) 2mg/kg was added to the platform. During COVID19 outbreak PBSCT was used as a graft source. Methods: Retrospective review of patients who underwent myeloablative Haplo-HCT for malignant hematologic disorders using ATG and PTCy for GvHD prophylaxis. Patient characteristics were summarized using frequencies for categorical variables and medians with ranges for continuous variables. Probabilities of overall survival (OS), relapsed-free survival (RFS) were summarized using Kaplan-Meier estimator with variance estimated using Greenwood’s formula. Survival curves were compared using the log-rank test. Probabilities of aGvHD, cGvHD, and extensive cGvHD were calculated using cumulative incidence function (CIF) taking into consideration DLI and death without GvHD. Probabilities of and relapse and non-relapsed mortality (NRM) were calculated using CIF taking into consideration death without GvHD and NRM and relapse as competing risks, respectively. Results: 60 patients were reviewed, 32 (53%) were males and 28 (47%) females. 57% had AML and 23% had ALL. Other diagnoses included CML, MDS, APL and BPDCN. 73% received BM graft and 27% PBSCT graft. The conditioning was myeloablative in the form of Thio/Bu/Flu (68%) for myeloid malignancies and Flu/TBI 1000 cGy (27%) for lymphoid malignancies. Most donors were males (57%) siblings (60%), with more than 50% HLA matching (58%), and no ABO mismatch (70%). Disease risk index (DRI) was intermediate in most cases (38%) followed by high (32%). At 5 years, the OS was 59% (95% CI: 46%-73%), RFS was 49% (95% CI: 34%-63%). 42% patients developed grade 2-4 aGvHD and 15% of patients developed extensive cGvHD. OS of patients > 50 years old was 21% (95% CI: 0%-56%). There were no cases of primary GF but 1 patient developed secondary GF. 17 patients developed HCYST (28%) and 17 (28%) needed ICU admission. Most patients (88%) developed CMV reactivation, and 2 patients developed VOD. We analyzed DRI, donor age, TBI vs. non-TBI, BM vs. PBSCT, donor relation, level of HLA matching, ABO mismatch, female vs. male donor, effects on OS, RFS and GvHD. None of these variables had significant association with OS. Higher DRI was associated with higher relapse (P0.04). Donor recipient sex mismatch and donor age were associated with cGvHD. Conclusions: Myeloablative Haplo-HCT for hematological malignancies with PTCy and ATG is safe and associated with acceptable OS, RFS and low rate of extensive cGvHD. Older patients require adjustment due to risk of higher NRM.
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