Amer Beitinjaneh

Reduced-intensity transplantation for lymphomas using haploidentical related donors vs HLA-matched unrelated donors

We evaluated 917 adult lymphoma patients who received haploidentical (n = 185) or HLA-matched unrelated donor (URD) transplantation either with (n = 241) or without antithymocyte globulin (ATG; n = 491) following reduced-intensity conditioning regimens. Haploidentical recipients received posttransplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis, whereas URD recipients received calcineurin inhibitor-based prophylaxis. Median follow-up of survivors was 3 years. The 100-day cumulative incidence of grade III-IV acute GVHD on univariate analysis was 8%, 12%, and 17% in the haploidentical, URD without ATG, and URD with ATG groups, respectively (P = .44). Corresponding 1-year rates of chronic GVHD on univariate analysis were 13%, 51%, and 33%, respectively (P < .001). On multivariate analysis, grade III-IV acute GVHD was higher in URD without ATG (P = .001), as well as URD with ATG (P = .01), relative to haploidentical transplants. Similarly, relative to haploidentical transplants, risk of chronic GVHD was higher in URD without ATG and URD with ATG (P < .0001). Cumulative incidence of relapse/progression at 3 years was 36%, 28%, and 36% in the haploidentical, URD without ATG, and URD with ATG groups, respectively (P = .07). Corresponding 3-year overall survival (OS) was 60%, 62%, and 50% in the 3 groups, respectively, with multivariate analysis showing no survival difference between URD without ATG (P = .21) or URD with ATG (P = .16), relative to haploidentical transplants. Multivariate analysis showed no difference between the 3 groups in terms of nonrelapse mortality (NRM), relapse/progression, and progression-free survival (PFS). These data suggest that reduced-intensity conditioning haploidentical transplantation with posttransplant cyclophosphamide does not compromise early survival outcomes compared with matched URD transplantation, and is associated with significantly reduced risk of chronic GVHD.

Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations in acute promyelocytic leukemia: A systematic review

The fms-like tyrosine kinase 3 (FLT3) gene aberrations, internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations, are frequent in acute promyelocytic leukemia (APL). To evaluate their prognostic significance, we performed a systematic review and meta-analysis. Eleven studies covering a total of 1063 subjects were included in this review. Incidence of ITD and TKD mutations was 12-38% and 2-20%, respectively. In 9 of 11 studies, ITD was associated with high WBC count at the time of diagnosis, which is a known prognostic indicator in APL. Patients with ITD had inferior 3-year overall survival compared to patients without ITD (risk ratio 1.42, 95% CI: 1.04-1.95). Similarly, ITD was also associated with adverse 3-year disease-free survival (risk ratio 1.48, 95% CI: 1.02-2.15). There were only two studies that evaluated the association of TKD mutation in APL; both showed a trend towards worse survival in patients with mutated TKD. In conclusion, FLT3 ITD is associated with high WBC at diagnosis in patients with APL. Although the available literature is limited to observational studies, our systematic review suggests that FLT3 mutations, especially ITD, can adversely affect overall survival and disease-free survival in APL.

Toxic Leukoencephalopathy following Fludarabine-Associated Hematopoietic Cell Transplantation

Toxic leukoencephalopathy has been more thoroughly investigated during the last decade because of the advance of magnetic resonance imaging (MRI) techniques. We analyzed fludarabine (Flu)-associated hematopoietic cell transplantation (HCT), resulting in severe leukoencephalopathy (n = 39/1596, 2.4%), and describe 3 clinical syndromes with unique clinical and radiographic characteristics. Posterior reversible encephalopathy syndrome (PRES) presents predominantly with seizures, persistent headache, and vision changes, along with variable mental status alterations. PRES is likely to be reversible, particularly after withholding cyclosporine (CsA). Acute toxic leukoencephalopathy (ATL) presents with cognitive dysfunction, decreased levels of consciousness, and vision changes. Other leukoencephalopathy (OLE) includes patients who behave similar to the ATL group, but with less prominent deep white matter changes on MRI. ATL and OLE are less likely to be reversible. The neurologic syndromes correlate with different MRI patterns. In PRES, subcortical and cortical involvement on MRI is associated with seizure, blurred vision, and dysarthria versus ATL and OLE, which involve deep white matter and cause mainly cognitive dysfunction. The different syndromes also carry different prognoses. All patients with Flu-associated encephalopathy had a median overall survival of only 169 days. Those with ATL had shorter overall survival (median 66 days) than patients with PRES (median 208 days). Potential risk factors for Flu-associated encephalopathy were older age, poor renal function, Flu dose, previously treated central nervous system (CNS) disease, or previous Flu-based transplant conditioning. Additional risk factors for PRES CNS toxicity are CsA use and acute hypertension. Flu pharmacokinetic studies may be useful to reduce life-threatening Flu-associated risks of neurotoxicity.

Increasing use of allogeneic hematopoietic cell transplantation in patients aged 70 years and older in the United States

In this study, we evaluated trends and outcomes of allogeneic hematopoietic cell transplantation (HCT) in adults ≥70 years with hematologic malignancies across the United States. Adults ≥70 years with a hematologic malignancy undergoing first allogeneic HCT in the United States between 2000 and 2013 and reported to the Center for International Blood and Marrow Transplant Research were eligible. Transplant utilization and transplant outcomes, including overall survival (OS), progression-free survival (PFS), and transplant-related mortality (TRM) were studied. One thousand one hundred and six patients ≥70 years underwent HCT across 103 transplant centers. The number and proportion of allografts performed in this population rose markedly over the past decade, accounting for 0.1% of transplants in 2000 to 3.85% (N = 298) in 2013. Acute myeloid leukemia and myelodysplastic syndromes represented the most common disease indications. Two-year OS and PFS significantly improved over time (OS: 26% [95% confidence interval (CI), 21% to 33%] in 2000-2007 to 39% [95% CI, 35% to 42%] in 2008-2013, P < .001; PFS: 22% [16% to 28%] in 2000-2007 to 32% [95% CI, 29% to 36%] in 2008-2013, P = .003). Two-year TRM ranged from 33% to 35% and was unchanged over time (P = .54). Multivariable analysis of OS in the modern era of 2008-2013 revealed higher comorbidity by HCT comorbidity index ≥3 (hazard ratio [HR], 1.27; P = .006), umbilical cord blood graft (HR, 1.97; P = .0002), and myeloablative conditioning (HR, 1.61; P = .0002) as adverse factors. Over the past decade, utilization and survival after allogeneic transplant have increased in patients ≥70 years. Select adults ≥70 years with hematologic malignancies should be considered for transplant.

Durable responses after donor lymphocyte infusion for patients with residual multiple myeloma following non-myeloablative allogeneic stem cell transplant

Abstract The role of donor lymphocyte infusion (DLI) in mediating the graft-versus-myeloma (GvM) effect after allogeneic hematopoietic stem cell transplant (allo-HCT) is not clearly defined. We evaluated the safety and utility of DLI in patients with either persistent or recurrent multiple myeloma (MM) after allo-HCT. Twenty-three patients with MM received DLI after allo-HCT at the University of Texas M. D. Anderson Cancer Center between July 1996 and June 2008. Eight patients received preemptive DLI for residual disease (RD) while 15 patients received DLI for the treatment of recurrent or progressive disease (PD). We evaluated the response to DLI and the factors that may predict a response. Median DLI dose was 3.3 × 107 CD3 + cells (range 0.5–14.8 × 107). Grade II–IV acute graft-versus-host disease (GvHD) was seen in five patients (22%). Median follow-up in surviving patients was 24 months. Five of 23 patients (22%) achieved a complete or a very good partial response (two CR, three VGPR), while eight patients (34%) had stable disease (SD) after the DLI. Patients who received DLI for RD had a higher response rate (≥ VGPR 50% vs. 7%, p = 0.03), a longer overall survival (28.3 vs. 7.6 months, p = 0.03) and a trend toward longer progression-free survival (11.9 vs. 5.2 months, p = 0.1). In this largest single institution study, we conclude that the use of preemptive, non-manipulated DLI for RD after reduced-intensity conditioning allo-HCT is encouraging, and it was associated with a higher response rate and a longer overall survival when given preemptively. The role of DLI needs to be further explored in prospective clinical trials.

Solid organ transplantation in survivors of hematopoietic cell transplantation: a single institution case series and literature review.

Beitinjaneh A, Burns LJ, Majhail NS. Solid organ transplantation in survivors of hematopoietic cell transplantation: a single institution case series and literature review.
Clin Transplant 2010: 24: E94–E102.
© 2009 John Wiley & Sons A/S.

Allogeneic Hematopoietic Cell Transplantation for Adult Chronic Myelomonocytic Leukemia

Allogeneic hematopoietic cell transplantation (HCT) is potentially curative for patients with chronic myelomonocytic leukemia (CMML); however, few data exist regarding prognostic factors and transplantation outcomes. We performed this retrospective study to identify prognostic factors for post-transplantation outcomes. The CMML-specific prognostic scoring system (CPSS) has been validated in subjects receiving nontransplantation therapy and was included in our study. From 2001 to 2012, 209 adult subjects who received HCT for CMML were reported to the Center for International Blood and Marrow Transplant Research. The median age at transplantation was 57 years (range, 23 to 74). Median follow-up was 51 months (range, 3 to 122). On multivariate analyses, CPSS scores, Karnofsky performance status (KPS), and graft source were significant predictors of survival (P = .004, P = .01, P = .01, respectively). Higher CPSS scores were not associated with disease-free survival, relapse, or transplantation-related mortality. In a restricted analysis of subjects with relapse after HCT, those with intermediate-2/high risk had a nearly 2-fold increased risk of death after relapse compared to those with low/intermediate-1 CPSS scores. Respective 1-year, 3-year, and 5-year survival rates for low/intermediate-1 risk subjects were 61% (95% confidence interval [CI], 52% to 72%), 48% (95% CI, 37% to 59%), and 44% (95% CI, 33% to 55%), and for intermediate-2/high risk subjects were 38% (95% CI, 28% to 49%), 32% (95% CI, 21% to 42%), and 19% (95% CI, 8% to 29%). We conclude that higher CPSS score at time of transplantation, lower KPS, and a bone marrow graft are associated with inferior survival after HCT. Further investigation of CMML disease-related biology may provide insights into other risk factors predictive of post-transplantation outcomes.

Phase II study of topotecan and bevacizumab in advanced, refractory non-small-cell lung cancer

BACKGROUND This clinical trial evaluated whether topotecan in combination with bevacizumab improved progression-free survival (PFS) in patients with advanced, refractory non--small-cell lung cancer in a second-line setting. PATIENT AND METHODS Patients aged 18 years old and older received topotecan (4.0 mg/m(2)) on days 1, 8, and 15, and bevacizumab (10 mg/kg) on days 1 and 15 as intravenous infusions on a 28-day treatment cycle. Available tumor specimens were analyzed for ISG15 gene expression as a biomarker of response to topotecan. RESULTS Forty-two patients were enrolled in the study, with a median age of 62.5 years and a median of 3 (range, 1-7) prior treatment regimens. Almost half (n = 18, 42.9%) of the patients received prior bevacizumab therapy. PFS was 5.1 months (95% CI, 3.7-7.8 months), and overall survival was 11.5 months (95% CI, 6.8-15.5 months). Response rates were as follows: 14.3% partial response, 54.8% stable disease, and 28.6% progressive disease. Hematologic toxicities included grade 3 thrombocytopenia (n = 7, 16.7%), neutropenia (n = 4, 9.5%), and anemia (n = 2, 4.8%). One toxic death occurred due to pulmonary hemorrhage, and one patient experienced a grade 4 pulmonary embolism. Grade 3 nonhematologic adverse events were uncommon (< 8%). There was a trend for improved median PFS, 3.5 months vs. 1.8 months (P = .26), in patients with high ISG15 expression. CONCLUSION Bevacizumab in combination with topotecan as a salvage therapy for metastatic non--small-cell lung cancer is well tolerated and is worthy of further investigation.

Post-Transplant Outcomes in High-Risk Compared with Non-High-Risk Multiple Myeloma: A CIBMTR Analysis.

Conventional cytogenetics and interphase fluorescence in situ hybridization (FISH) identify high-risk multiple myeloma (HRM) populations characterized by poor outcomes. We analyzed these differences among HRM versus non-HRM populations after upfront autologous hematopoietic cell transplantation (autoHCT). Between 2008 and 2012, 715 patients with multiple myeloma identified by FISH and/or cytogenetic data with upfront autoHCT were identified in the Center for International Blood and Marrow Transplant Research database. HRM was defined as del17p, t(4;14), t(14;16), hypodiploidy (<45 chromosomes excluding -Y) or chromosome 1 p and 1q abnormalities; all others were non-HRM. Among 125 HRM patients (17.5%), induction with bortezomib and immunomodulatory agents (imids) was higher compared with non-HRM (56% versus 43%, P < .001) with similar pretransplant complete response (CR) rates (14% versus 16%, P .1). At day 100 post-transplant, at least a very good partial response was 59% in HRM and 61% in non-HRM (P = .6). More HRM patients received post-transplant therapy with bortezomib and imids (26% versus 12%, P = .004). Three-year post-transplant progression-free (PFS) and overall survival (OS) rates in HRM versus non-HRM were 37% versus 49% (P < .001) and 72% versus 85% (P < .001), respectively. At 3 years, PFS for HRM patients with and without post-transplant therapy was 46% (95% confidence interval [CI], 33 to 59) versus 14% (95% CI, 4 to 29) and in non-HRM patients with and without post-transplant therapy 55% (95% CI, 49 to 62) versus 39% (95% CI, 32 to 47); rates of OS for HRM patients with and without post-transplant therapy were 81% (95% CI, 70 to 90) versus 48% (95% CI, 30 to 65) compared with 88% (95% CI, 84 to 92) and 79% (95% CI, 73 to 85) in non-HRM patients with and without post-transplant therapy, respectively. Among patients receiving post-transplant therapy, there was no difference in OS between HRM and non-HRM (P = .08). In addition to HRM, higher stage, less than a CR pretransplant, lack of post-transplant therapy, and African American race were associated with worse OS. In conclusion, we show HRM patients achieve similar day 100 post-transplant responses compared with non-HRM patients, but these responses are not sustained. Post-transplant therapy appeared to improve the poor outcomes of HRM.

Survival and Late Effects after Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancy at Less than Three Years of Age

Very young children undergoing hematopoietic cell transplantation (HCT) are a unique and vulnerable population. We analyzed outcomes of 717 patients from 117 centers who survived relapse free for ≥1 year after allogeneic myeloablative HCT for hematologic malignancy at <3 years of age, between 1987 and 2012. The median follow-up was 8.3 years (range, 1.0 to 26.4 years); median age at follow-up was 9 years (range, 2 to 29 years). Ten-year overall and relapse-free survival were 87% (95% confidence interval [CI], 85% to 90%) and 84% (95% CI, 81% to 87%). Ten-year cumulative incidence of relapse was 11% (95% CI, 9% to 13%). Of 84 deaths, relapse was the leading cause (43%). Chronic graft-versus-host-disease 1 year after HCT was associated with increased risk of mortality (hazard ratio [HR], 2.1; 95% CI, 1.3 to 3.3; P = .0018). Thirty percent of patients experienced ≥1 organ toxicity/late effect >1 year after HCT. The most frequent late effects included growth hormone deficiency/growth disturbance (10-year cumulative incidence, 23%; 95% CI, 19% to 28%), cataracts (18%; 95% CI, 15% to 22%), hypothyroidism (13%; 95% CI, 10% to 16%), gonadal dysfunction/infertility requiring hormone replacement (3%; 95% CI, 2% to 5%), and stroke/seizure (3%; 95% CI, 2% to 5%). Subsequent malignancy was reported in 3.6%. In multivariable analysis, total body irradiation (TBI) was predictive of increased risk of cataracts (HR, 17.2; 95% CI, 7.4 to 39.8; P < .001), growth deficiency (HR, 3.5; 95% CI, 2.2 to 5.5; P < .001), and hypothyroidism (HR, 5.3; 95% CI, 3.0 to 9.4; P < .001). In summary, those who survived relapse free ≥1 year after HCT for hematologic malignancy at <3 years of age had favorable overall survival. Chronic graft-versus-host-disease and TBI were associated with adverse outcomes. Future efforts should focus on reducing the risk of relapse and late effects after HCT at early age.