A. Dagis

Iron overload adversely affects outcome of allogeneic hematopoietic cell transplantation

Iron overload is common in patients undergoing allogeneic hematopoietic cell transplantation (HCT) for hematologic disorders. Serum ferritin, a marker of tissue iron overload, was measured immediately before transplant in adult patients undergoing myeloablative HCT from matched sibling or unrelated donors. The effect of elevated pretransplant ferritin (defined as ferritin ⩾1000 ng/ml) on day 100 mortality, overall survival, acute GVHD and infectious complications was assessed. Data on 190 patients were analyzed. In univariate analysis, the high-ferritin group had increased day 100 mortality (20 vs 9%, P=0.038), decreased overall survival (log-rank test: P-value=0.004), increased acute GVHD/death (63 vs 43%, P=0.009) and increased incidence of blood stream infections (BSIs)/death (60 vs 44%, P=0.042). In a multivariate analysis, high ferritin was associated with increased risk of death (Cox model: hazard ratio=2.28, P=0.004), increased day 100 mortality (generalized linear model (GLM) odds ratio=3.82, P=0.013), increased incidence of acute GVHD/death (GLM odds ratio=3.11, P=0.001) and increased risk of BSI/death (GLM odds ratio=1.99, P=0.032). The results remained similar when serum ferritin was considered a continuous variable. Elevated serum ferritin adversely impacts on overall survival and increases the likelihood of acute GVHD and BSI after allogeneic HCT.

Killer Ig-like receptor (KIR) compatibility plays a role in the prevalence of acute GVHD in unrelated hematopoietic cell transplants for AML

Summary:Killer Ig-like receptor (KIR) is a major cluster of the natural killer cell receptors and may play a role in the outcome of hematopoietic cell transplants. A total of 65 AML cases transplanted with T-replete hematopoietic cells from unrelated donors were retrospectively KIR-genotyped by a multiplex PCR method of our own design. The KIR gene frequency and genotype patterns in these 130 samples were consistent with the data in the literature. Based upon overall inhibitory and activating KIR genes in both donors and patients, we developed an algorithm to calculate a compatibility score for each transplant case as plus, zero or minus. Significantly higher incidence (18/20, 90%) of acute (a) GVHD (grade II–IV) was found in the transplant cases with plus scores than that (25/45, 56%) in the cases with zero or minus scores (P<0.01). When the scores are sorted in the opposite way, fewer cases (13/26, 50%) of aGVHD were found in the transplants with minus scores than that (30/39, 77%) in the transplants with zero or plus scores (P<0.05). The difference of aGVHD prevalence between the plus score and minus score groups is highly significant (P<0.01). KIR genotype compatibility calculated by this algorithm may predict aGVHD incidence and be helpful in choosing donors.

Therapy-related ALL: cytogenetic features and hematopoietic cell transplantation outcome

Therapy-related leukemia has been described after chemotherapy, radiation and autologous hematopoietic SCT. The majority of such cases are therapy-related AML/myelodysplastic syndrome (t-AML/MDS) and the cytogenetic and molecular features of these cases are well defined. On the other hand, therapyrelated ALL (t-ALL) has been described infrequently in the literature. The clinical and pathological characteristics as well as treatment outcomes of t-ALL remain poorly defined. Although mixed myeloid leukemia (MLL) gene rearrangement is the most recurrent cytogenetic abnormality associated with t-ALL in the literature, other chromosomal alterations have been described. Herein, we examined the pathologic features and treatment outcomes of a cohort of t-ALL patients who underwent allogeneic hematopoietic cell transplantation (HCT) at our institution in order to better characterize the cytogenetic profile of t-ALL, and to examine outcomes of t-ALL post allogeneic HCT. We reviewed a consecutive case series of adult ALL patients who underwent allogeneic HCT at City of Hope between 1998 and 2014. We excluded patients with prior malignancies who did not receive chemotherapy or/and radiation before ALL onset. Continuous variables were tested between the leukemia cytogenetic abnormality subgroups, namely MLL gene rearrangement-positive and Phpositive, and others (all cases excluding those with MLL gene rearrangement and Ph chromosome) using the Wilcoxon ranksum test. Categorical variables were tested using Fisher’s exact test. Survival estimates were calculated from the date of transplantation, and tested using the log-rank test of Mantel and Haenszel for OS and leukemia-free survival (LFS). Cumulative incidence of relapse (CIR) with non-relapse-related mortality (NRM) as a competing risk was plotted and tested using prevalence methods developed by Gray. Among 596 adults with ALL who underwent allogeneic HCT during the specified period, we identified 28 (4.7%) patients who had a history of chemotherapy and/or radiation before the diagnosis of ALL. The median age was 48 years (range 29–61), and 57% of patients were female. All cases had B-cell phenotype. The median initial WBC was 8.0 × 10/L (range 1.2–323). The median interval from initial diagnosis of malignancy/disease to ALL diagnosis was 7.3 years (range 0.9–50.1). The most common prior diagnosis was breast cancer (N= 9), and this was followed by multiple myeloma (N= 4), sarcoma (N= 4), thyroid cancer/disease (N= 4), lymphoma (N= 3), germ cell tumor (N= 2, including a case of combined germ cell and CLL), melanoma (N= 1) and colon cancer (N= 1). Twenty-nine percent (N= 8) had a prior combination of chemotherapy and radiation therapy, 32% (N= 9) had prior radiation alone and 39% (N= 11) had prior chemotherapy alone. Four patients (14%) had undergone autologous HCT prior to ALL diagnosis. Interestingly, the most common cytogenetic abnormality in our cohort was t(9;22)(q34;q11) (Ph chromosome) in 39% (N= 11) followed by MLL gene rearrangement in 25% (N= 7). MLL gene rearrangement were t(4;11) (N= 5), t(6;11) (N= 1) and t(1;11) (N= 1). Other observed cytogenetics include three cases of normal karyotype and single case of each of the following: complex karyotype; hypodiploidy; 14q32/IGH+; t(1;5); t(12;17); t(1;19); and t(2;7). Therefore, we compared the clinical and pathological features of the three main cytogenetic subgroups: Ph+ t-ALL vs MLL gene-rearranged t-ALL vs t-ALL with other cytogenetic abnormalities. The median age, initial WBC and the type of previous cytotoxic modality were similar among the three cytogenetic subgroups. However, the median interval from the diagnosis of previous malignancy to ALL diagnosis was significantly longer for Ph+ t-ALL and other cytogenetics subgroups compared with the MLL generearrangement subgroup (9.37 vs 7.96 vs 2.07 years; P= 0.0006, respectively; Table 1). The majority of patients were in CR1 at the time of transplantation (71%). Conditioning regimen for HCT was full intensity in 16 patients (57%). Tacrolimus/sirolimus-based GVHD prophylaxis was used in 16 patients (57%). Unrelated donor was the source of graft in 15 patients (54%) and mobilized peripheral blood progenitor cells were used in 23 patients (82%). Disease status at transplant, time from diagnosis to HCT, source of graft, GVHD prophylaxis and conditioning intensity were not different among the cytogenetic subgroups. The 4-year LFS, OS, CIR and NRM for the whole cohort were 47%, 51%, 28% and 25%, respectively. For the patients transplanted in CR1 (N= 20), the 4-year LFS, OS and CIR were 58%, 65% and 23%, respectively, and LFS (P= 0.008) and OS (P= 0.02) were significantly higher for patients transplanted in CR1 compared with those transplanted in non-CR1 (N= 8). Outcomes were not different among the three cytogenetic subgroups (Figure 1). One patient experienced relapse of the initial malignancy (CLL) after allogeneic HCT for t-ALL. Given the fact that t-ALL constitutes a distinct minority among therapy-related leukemias, our study describes a relatively large number of t-ALL treated uniformly with alloHCT. Furthermore, we describe the cytogenetic features of this rare ALL subset and confirm the existence of therapy-related Ph+ ALL as a distinct entity. There are case reports as well as a small case series in the published literature describing the outcome of secondary ALL. However, not all these cases have received prior cytotoxic therapy, and hence, it is difficult to establish a causal relationship between therapy of the prior malignancy and subsequent occurrence of ALL in all of these cases. In contrast, we restricted the definition of t-ALL to cases with prior exposure to chemotherapy or/and radiation. The GIMEMA group identified 21 (2.3%) cases of secondary ALL among 901 adults with ALL recorded in the database, but only 11 patients had prior treatment with cytotoxic therapy before ALL diagnosis. The median latency to development of secondary ALL from prior malignancy diagnosis was 27 months. Normal karyotype was the most common reported cytogenetic characteristic, but Ph chromosome was seen in three cases. The median survival was only 5 months. Shivakumar et al. pooled 101 cases of secondary ALL reported in the literature between the years 1982 and 2005, including 12 cases with no prior cytotoxic therapy. MLL gene rearrangement (N= 37) was the most commonly Bone Marrow Transplantation (2015) 50, 746–748

Phase-2 Trial of an Intensified Conditioning Regimen for Allogeneic Hematopoietic Cell Transplant for Poor-Risk Leukemia

Patients with poor-risk leukemia have a high relapse rate despite allogeneic transplant. We report on the phase-2 trial of an intensified allogeneic transplant regimen whose aim was tolerable toxicity and durable remission. Study patients (n=30) had unfavorable first remission cytogenetics, progression from myelodysplasia or active disease due to induction failure or relapse. Conditioning was i.v. BU, targeted to a first-dose plasma area under the curve (AUC) of 700–900 μM min, VP-16 at 30 mg/kg of adjusted ideal body weight and fractionated TBI (FTBI) at 1200 cGy in 10 fractions. GVHD prophylaxis was CsA and mycophenolate mofetil. Regimen-related toxicities (Bearman) included grade II mucositis in 29 patients (97%) and grade III in one patient, grade II–III sinusoidal obstructive syndrome in 2 patients (7%), and grade 2–3 (CTC) skin toxicity in 8 patients (27%). The 30- and 100-day TRMs were 0 and 7% respectively. The median follow-up was 83.7 months (60.7–96.4) for surviving patients. The 5-year overall and disease-free survival was 40% for all patients. Cumulative 5-year relapse incidence (RI) was 23% and TRM was 37%. We have shown promising OS and RI in these poor-risk patients, who typically have few curative options.