Fabian Lang

Mismatched unrelated hematopoietic stem cell transplantation with post-transplant cyclophosphamide for high-risk acute myeloid leukemia

Dear Editor, Patients with high-risk acute myeloid leukemia (AML) who lack an at least 9/10 HLA-allele matched donor are considered candidates for an HLA-haploidentical family donor bone marrow transplantation (BMT) with posttransplantation cyclophosphamide (PT-Cy) as graftversus-host (GvHD) prophylaxis [1]. PT-Cy is known to preferentially eliminate alloreactive cells, preserve regulatory T cells, and has proven to be safe and effective in preventing acute and chronic GvHD [2]. Despite encouraging results in the setting of haploidentical [3–5] and also matched donor transplants [6], the feasibility of using PT-Cy after a mismatched unrelated donor (MMUD, i.e., discrepancies in 2/10 HLA loci) BMT [7] has to date not been reported. Between June 2012 and June 2015, 11 consecutive patients with high-risk AML were grafted with unmanipulated bone marrow from a haploidentical family donor (n = 6) or—if such a donor was unavailable—a MMUD (n = 5) using cyclophosphamide (50 mg/kg on days +3 and +5) in addition to cyclosporine A and mycofenolate mofetil irrespective of donor type. Myeloablative conditioning consisted of TBF (n = 10, i.e., 2 × 5 mg/kg thiotepa, 2–3 × 3.2 mg/kg busulfan i.v. and 3 × 50 mg/m fludarabine) or F-TBI (n = 1, i.e., 6 × 2 Gy total body irradiation and 3 × 50 mg/m fludarabine) [8]. This retrospective analysis was approved by the local ethics committee (321/15), and informed consent was obtained from all patients. Detailed patient demographics, clinical characteristics, and outcome parameters are listed in Table 1. All patients engrafted promptly; recovery of neutrophils and platelets did not differ between the MMUD and haploidentical group. By competing risk analysis, the estimated CI of acute GvHD II– IV and III–IV was 45 and 18 %, respectively. Acute GvHD was steroid-responsive in all but one patient in the haploidentical group. Of note, we observed no severe chronic GvHD or deaths from transplant-related complications; the estimated CI of moderate chronic GvHD at 1 year was 30 % (one in the haploidentical, two in the MMUD group). Haploidentical as well as MMUD grafts facilitated an early lymphocyte recovery with an absolute lymphocyte count >300/μL on day 60 post-BMT in all cases, parameters which have recently been associated with low treatment-related mortality and favorable outcome [9]. With a median follow-up of surviving patients of 15 months, overall and relapse-free survival probabilities at 1 and 2 years were 80 and 82 %, respectively. Two patients in the haploidentical and none in the MMUD group relapsed and died. The two relapses occurred in patients transplanted in MRD-positive CR1 and refractory relapse after previous hematopoietic stem cell transplantation (HSCT), respectively. Although the follow-up is still short, these outcomes are in line with a recently published survey * Gesine Bug g.bug@em.uni-frankfurt.de

Genomic CDKN2A/2B deletions in adult Ph+ ALL are adverse despite allogeneic stem cell transplantation

We investigated the role of copy number alterations to refine risk stratification in adult Philadelphia chromosome positive (Ph)+ acute lymphoblastic leukemia (ALL) treated with tyrosine kinase inhibitors (TKIs) and allogeneic stem cell transplantation (aSCT). Ninety-seven Ph+ ALL patients (median age 41 years; range 18-64 years) within the prospective multicenter German Multicenter ALL Study Group studies 06/99 (n = 8) and 07/2003 (n = 89) were analyzed. All patients received TKI and aSCT in first complete remission (CR1). Copy number analysis was performed with single nucleotide polymorphism arrays and validated by multiplex ligation-dependent probe amplification. The frequencies of recurrently deleted genes were: IKZF1, 76%; CDKN2A/2B, 45%; PAX5, 43%; BTG1, 18%; EBF1, 13%; ETV6, 5%; RB, 14%. In univariate analyses, the presence of CDKN2A/2B deletions had a negative impact on all endpoints: overall survival (P = .023), disease-free survival (P = .012), and remission duration (P = .036). The negative predictive value of CDKN2A/2B deletions was retained in multivariable analysis along with other factors such as timing of TKI therapy, intensity of conditioning, achieving remission after induction phase 1 and BTG1 deletions. We therefore conclude that acquired genomic CDKN2A/2B deletions identify a subgroup of Ph+ ALL patients, who have an inferior prognosis despite aSCT in CR1. Their poor outcome was attributable primarily to a high relapse rate after aSCT.

Plastic CD34 and CD38 expression in adult B-cell precursor acute lymphoblastic leukemia explains ambiguity of leukemia-initiating stem cell populations.

Plastic CD34 and CD38 expression in adult B–cell precursor acute lymphoblastic leukemia explains ambiguity of leukemia-initiating stem cell populations

Dasatinib and Azacitidine Followed by Haploidentical Stem Cell Transplant for Chronic Myeloid Leukemia with Evolving Myelodysplasia: A Case Report and Review of Treatment Options

Patient: Female, 41 Final Diagnosis: CML with myelodysplasia Symptoms: Fatigue Medication: Dasatinib • Azacitidine Clinical Procedure: Haploidentical stem cell transplantation Specialty: Hematology Objective: Rare co-existance of disease or pathology Background: CML presenting with a variant Philadelphia translocation, atypical BCR-ABL transcript, additional chromosomal aberrations, and evolving MDS is uncommon and therapeutically challenging. The prognostic significance of these genetic findings is uncertain, even as singular aberrations, with nearly no data on management and outcome when they coexist. MDS evolving during the course of CML may be either treatment-associated or an independently coexisting disease, and is generally considered to have an inferior prognosis. Tyrosine kinase inhibitors (TKI) directed against BCR-ABL are the mainstay of treatment for CML, whereas treatment modalities that may be utilized for MDS and CML include allogeneic stem cell transplant and – at least conceptually – hypomethylating agents. Case Report: Here, we describe the clinical course of such a patient, demonstrating that long-term combined treatment with dasatinib and azacitidine for coexisting CML and MDS is feasible and well tolerated, and may be capable of slowing disease progression. This combination therapy had no deleterious effect on subsequent potentially curative haploidentical bone marrow transplantation. Conclusions: The different prognostic implications of this unusual case and new therapeutic options in CML are discussed, together with a review of the current literature on CML presenting with different types of genomic aberrations and the coincident development of MDS. Additionally, this case gives an example of long-term combined treatment of tyrosine kinase inhibitors and hypomethylating agents, which could be pioneering in CML treatment.