Hassan Sibai

Managing Hodgkin lymphoma relapsing after autologous hematopoietic cell transplantation: a not-so-good cancer after all!

Hodgkin lymphoma (HL) relapsing after an autologous hematopoietic cell transplant (HCT) poses a therapeutic challenge. In this setting, salvage chemotherapy (for example, gemcitabine-based, ifosfamide-containing and others) or immunotherapy (for example, brentuximab vedotin) is essential as a bridging-cytoreduction strategy to an allogeneic HCT. Myeloablative allogeneic hematopoietic cell transplantation in relapsed HL is associated with high rates of non-relapse mortality. In carefully selected patients with chemosensitive disease, allografting following lower-intensity conditioning regimens can provide durable disease control rates of about 25–35%. Promising early results with haploidentical and umbilical cord transplantation are noteworthy and are expanding this procedure to patients for whom HLA-matched related or unrelated donors are not available. Unfortunately, a significant number of HL patients relapsing after an autologous HCT are not candidates for allografting because of the presence of resistant disease, donor unavailability or comorbidities. Brentuximab vedotin is approved for HL relapsing after a prior autograft. Rituximab and bendamustine are also active in this setting, albeit with short durations of remission. Histone deacetylase inhibitors (for example, panobinostat, mocetinostat), mTOR inhibitors (for example, everolimus) and immunomodulatory agents (lenalidomide) have shown activity in phase II trials, but currently are not approved for this indication. Second autologous HCT are rarely performed but this approach should not be considered standard practice at this time. The need for effective agents for post autograft failures of HL largely remains unmet. Continuous efforts to ensure early referral of such patients for allogeneic HCT or investigational therapies are the key to improving outcomes of this not-so-good lymphoma.

Ponatinib in the therapy of chronic myeloid leukemia

ABSTRACT Introduction: Chronic Myeloid Leukemia (CML) is a myeloproliferative disorder that has become the neoplastic poster child for understanding the disease biology of a malignant disease and targeting effective therapy. The targeted therapy of BCR-ABL inhibition by tyrosine kinase inhibitors (TKI) has provided the epitome for “Ehlrich’s magic bullet” postulated decades ago. Areas covered: Due to the therapy with these drugs, the survival of newly diagnosed patients with this disease now approaches that of age matched controls. Progression to advanced phases of CML had decreased over the years, though resistance has now been increasingly identified. Expert commentary: Ponatinib is a third generation TKI, which has shown to be effective in both early and advanced phases of CML and those bearing resistant mutations, specifically T315I. However, new side effect considerations need to be balanced with the efficacy, to establish the role of ponatinib in the therapy of CML.

Myeloablative versus Reduced-Intensity Conditioning in Patients with Myeloid Malignancies: A Propensity Score-Matched Analysis

Reduced-intensity conditioning (RIC) has been shown to have similar overall survival (OS) but higher relapse rates compared with myeloablative (MAC) regimens in patients with myeloid malignancies undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Using propensity score matching (PSM) analysis, well-balanced pairs of different variables can be compared effectively. We retrospectively compared allo-HSCT recipients with acute myeloid leukemia or myelodysplasia receiving a RIC regimen (FBT200; fludarabine 30 mg/m2/day for 4 days, busulfan 3.2 mg/kg/day for 2 days, and total body irradiation [TBI] 200 cGy) or MAC regimen (FBT400; fludarabine 50 mg/m2/day for 4 days, busulfan 3.2 mg/kg/day for 4 days, and TBI 400 cGy). A total of 248 patients (121 in the RIC group and 127 in the MAC group) were included in the analysis. No statistically significant difference was observed in 2-year OS (RIC group, 45.2 ± 5.0%; MAC group, 51.7 ± 5.2%; P = .541), nonrelapse mortality (NRM; RIC group, 28.7 ± 2.8% MAC group, 34.7 ± 4.6%; P = .368), and acute graft-versus-host disease (GVHD) (P = .171) or chronic GVHD (P = .605) at 1 year. The cumulative incidence of relapse (CIR) at 2 years was statistically significantly different between the 2 groups, however (RIC, 26.1 ± 2.6%; MAC, 14.2 ± 3.5%; P = .033). When PSM was applied to the study population, 42 case-control pairs were evenly matched. PSM analysis confirmed no statistically significant difference in 2-year OS (RIC, 49.0 ± 9.1%; MAC, 54.9 ± 7.7%; P = .718), NRM (RIC, 22.2 ± 2.3%; MAC, 33.3 ± 2.8%; P = .238), or CIR (RIC, 25.7 ± 2.6%; MAC, 9.5 ± 1.1%; P = .315) in the PSM pairs. Our findings demonstrate that after applying PSM, FBT 200 RIC conditioning has comparable OS, NRM, and CIR to FBT 400 MAC conditioning before allo-HSCT.

Venous thromboembolism prevention during asparaginase-based therapy for acute lymphoblastic leukemia.

BACKGROUND Venous thromboembolism (vte) is a recognized complication in patients treated with asparaginase-containing chemotherapy regimens; the optimal preventive strategy is unclear. We assessed the safety and efficacy of prophylaxis using low-dose low molecular weight heparin in adult patients with acute lymphoblastic leukemia in complete remission treated with an asparaginase-based post-remission chemotherapy regimen. METHODS As part of the intensification phase of the Dana-Farber Cancer Institute 91-01 regimen, asparaginase was administered weekly to 41 consecutive patients for 21-30 weeks; these patients also received prophylaxis with enoxaparin 40 mg daily (60 mg for patients ≥80 kg). Outcomes were assessed against outcomes in a comparable cohort of 99 patients who received the same chemotherapy regimen without anticoagulation prophylaxis. RESULTS The overall rate of symptomatic venous thrombosis was not significantly different in the prophylaxis and non-prophylaxis cohorts (18.92% and 21.74% respectively). Among patients receiving prophylaxis, vte occurred in higher proportion in those who weighed at least 80 kg (42.86% vs. 4.35%, p = 0.0070). No major bleeding complications occurred in the prophylaxis group (minor bleeding: 8.1%). CONCLUSIONS Prophylaxis with low-dose enoxaparin during the intensification phase was safe, but was not associated with a lower overall proportion of vte.

Haematopoietic cell transplantation for blastic plasmacytoid dendritic cell neoplasm: a North American multicentre collaborative study

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is incurable with conventional therapies. Limited retrospective data have shown durable remissions after haematopoietic cell transplantation (HCT) [allogeneic (allo) or autologous (auto)]. We conducted a multicentre retrospective study in BPDCN patients treated with allo‐HCT and auto‐HCT at 8 centres in the United States and Canada. Primary endpoint was overall survival (OS). The population consisted of 45 consecutive patients who received an allo‐HCT (n = 37) or an auto‐HCT (n = 8) regardless of age, pre‐transplant therapies, or remission status at transplantation. Allo‐HCT recipients were younger (50 (14–74) vs. 67 (45–72) years, P = 0·01) and had 1‐year and 3‐year OS of 68% [95% confidence interval (CI) = 49–81%] and 58% (95% CI = 38–75%), respectively. Allo‐HCT in first complete remission (CR1) yielded superior 3‐year OS (versus not in CR1) [74% (95% CI = 48–89%) vs. 0, P < 0·0001]. Allo‐HCT outcomes were not impacted by regimen intensity [3‐year OS for myeloablative conditioning = 61% (95% CI = 28–83%) vs. reduced‐intensity conditioning = 55% (95% CI = 28–76%)]. One‐year OS for auto‐HCT recipients was 11% (95% CI = 8–50%). These results demonstrate efficacy of allo‐HCT in BPDCN, especially in patients in CR1. Pertaining to auto‐HCT, our results suggest lack of efficacy against BPDCN, but this observation is limited by the small sample size. Larger prospective studies are needed to better define the role of HCT in BPDCN.

Impact of genomic alterations on outcomes in myelofibrosis patients undergoing JAK1/2 inhibitor therapy

In myelofibrosis (MF), driver mutations in JAK2, MPL, or CALR impact survival and progression to blast phase, with the greatest risk conferred by triple-negative status. Subclonal mutations, including mutations in high-molecular risk (HMR) genes, such as ASXL1, EZH2, IDH1/2, and SRSF2 have also been associated with inferior prognosis. However, data evaluating the impact of next-generation sequencing in MF patients treated with JAK1/2 inhibitors are lacking. Using a 54-gene myeloid panel, we performed targeted sequencing on 100 MF patients treated with ruxolitinib (n = 77) or momelotinib (n = 23) and correlated mutational profiles with treatment outcomes. Ninety-nine patients had at least 1 mutation identified, 46 (46%) had 2 mutations, and 34 (34%) patients had ≥3 mutations. Seventy-nine patients carried a mutation in JAK2V617F, 14 patients had mutations in CALR, 6 patients had an MPL mutation, and 2 patients were triple negative. No mutation was significantly associated with spleen or anemia response. A high Dynamic International Prognostic Scoring System score and pretreatment transfusion dependence were associated with a shorter time to treatment failure (TTF), and this association retained significance on multivariable analysis. Patients with ASXL1 (hazard ratio [HR], 1.86; P = .03) and EZH2 mutations (HR, 2.94; P = .009) and an HMR profile (HR, 2.06; P = .01) had shorter TTF. On multivariate analysis, ASXL1 or EZH2 mutations were independently associated with shorter TTF and overall survival. These findings help identify patients unlikely to have a durable response with current JAK1/2 inhibitors and provide a framework for future studies.

A critical review of treatment modalities for blastic plasmacytoid dendritic cell neoplasm

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a clinically aggressive tumor derived from the precursors of plasmacytoid dendritic cells. It is a rare disease presenting across all ages with either skin or both skin and bone marrow involvement often conferring a poor prognosis. Though localized radiation has been used before, acute leukemia based regimens, remains the treatment of choice for induction of remission. Hematopoietic stem cell transplant, either autologous or allogeneic, is further required for attaining sustained remissions. Recently, a number of targeted therapies and newer drugs have been used as the molecular and genetic understanding of the disease have improved.

AML refractory to primary induction with Ida-FLAG has a poor clinical outcome

We evaluated outcomes of 100 patients with high risk AML treated with Ida-FLAG induction as first-line therapy. 72 achieved remission with one cycle; 19 did not. High risk cytogenetics and TP53 mutations were associated with failure to achieve remission. In those reaching remission, allogeneic bone marrow transplantation was associated with better relapse-free and overall survival. Those not achieving remission with induction therapy were extremely unlikely to reach remission with further therapy and had a dismal prognosis. Exploratory molecular analysis confirmed persistence of the dominant genetic mutations identified at diagnosis. Ex vivo chemosensitivity did not demonstrate significant differences between responders and non-responders. Thus, Ida-FLAG induction has a high chance of inducing remission in patients with high risk AML. Those achieving remission require allogeneic transplantation to achieve cure; those not achieving remission rarely respond to salvage chemotherapy and have a dismal outcome. Alternatives to conventional chemotherapy must be considered in this group.

Remissions after third induction chemotherapy for primary non-responders with acute myeloid leukemia (AML) are uncommon and short-lived

Approximately 20–30% of adult patients with acute myeloid leukemia (AML) will not achieve complete remission (CR) with induction and re-induction chemotherapy and are classified as ‘primary non-responders’ [1]. Currently, there is no widely accepted standard of care for management of AML with primary induction failure and the prognosis of these patients remains poor. Based on the clinical circumstances and the availability of therapeutic options, these patients may undergo salvage allogeneic stem cell transplantation (SCT), or receive subsequent courses of intensive chemotherapy, experimental therapies, or palliation [2]. SCT offers the potential of long-term remission for patients with high risk AML, but the utility of SCT for patients who have not attained CR is controversial [3–7]. Thus, a third course of induction chemotherapy is sometimes offered to primary non-responders with AML with the goal to induce CR prior to SCT [8]. However, to our knowledge, the rate of CR and the clinical outcome following this approach has not been reported in the literature. In this retrospective chart review, we investigated the survival outcome of all primary non-responders with AML (n1⁄4 95) who underwent a third course of induction chemotherapy or received non-induction therapies and/or palliative care at Princess Margaret Cancer Centre between May 1999 and March 2015. Treatment failure was defined based on recommendations of the European Leukemia Network (ELN 2017) for response criteria in AML. Briefly, patients were classified as ‘primary non-responders’ if they did not achieve CR or CR with incomplete hematologic recovery (CRi) following their first and second course of induction chemotherapy and did not die in aplasia or due to an indeterminate cause (as per ELN definitions) prior to response determination [9]. Best response to treatment following each line of intensive chemotherapy was determined on Day 28 or later post-completion of the chemotherapy course. Overall survival (OS) following each induction course was defined as the time from the start of the induction until the date of last follow-up or of death from any cause. Patients with acute promyelocytic leukemia (APL) and chronic myeloid leukemia (CML) in blast crises were excluded from the analysis. Differences in baseline characteristics were examined by Fisher’s exact test for categorical variables and Wilcoxon rank-sum test for continuous variables. Mantel–Cox log-rank test was used to compare the survival functions. Two sided tests were used for all statistical analyzes. p values <.05 were considered statistically significant. Stata version 11.1 (College Station, TX) was used for all analyzes. Induction and re-induction protocols consisted of ‘7þ 3’ regimen [cytarabineþdaunorubicin (or amsacrine for patients with LVEF 40–49%)], Nove-HiDAC (mitoxantroneþ etoposideþ cytarabine), Flag-Ida (fludarabineþ cytarabineþG-CSFþ idarubicin), or combinations of 7þ 3 or Nove-HiDAC with investigational agents. No patients received the same regimen for both induction and reinduction. Median age of the 95 non-responders was 58.3 years (range: 20–76.6). Forty eight (50%) were male. Forty eight (50%) were male. Sixty-two percent had de novo AML, 20% had AML secondary to MDS or MPN and 18% had therapy related AML. Forty-six percent of these patients had an adverse cytogenetic risk profile, 38% had intermediate (normal karyotype 20%), and 2% had favorable cytogenetics. From the first day of the second induction regimen, the median OS for the 95 primary non-responders was 170 days (range: 20–1855). Nineteen patients died in hospital during the admission for the second induction with a median OS of 64 days (range 20–190) after the start of the second induction. Three of these 19 patients died within the first 30 days following the second induction. Seventy six of 95 primary non-responders survived the immediate post-induction period and were discharged from the hospital following completion of the second induction. Of these, 14 patients subsequently received a

Distribution and Impact of Comorbidities on Survival and Leukemic Transformation in Myeloproliferative Neoplasm-Associated Myelofibrosis: A Retrospective Cohort Study

Background We sought to describe the distribution and impact of comorbidities on outcomes in patients with myelofibrosis, a disease characterized by aberrant bone marrow function with eventual fibrosis. Comorbidities were scored using the Adult Comorbidity Evaluation‐27 (ACE‐27) and the Hematopoietic Cell Transplant Comorbidity Index (HCT‐CI), in which a score ≥ 3 indicates severe comorbidities. Patients and Methods We conducted a retrospective study of 306 patients with a confirmed diagnosis of myelofibrosis. Patients were seen from 1999 to 2014 with a median follow‐up of 2 years. Multivariable Cox proportional hazards models were constructed to assess the impact of comorbidities on overall survival and leukemic transformation from the date of presentation to our center. A series of descriptive analyses were performed examining the distribution of comorbidities captured by the scales. Results On multivariable survival analysis, an ACE‐27 score of 3 was associated with an almost twofold increase in the risk of all‐cause death (hazard ratio [HR] 1.95; 95% confidence interval [CI], 1.06‐3.58; P = .03) compared with a lower score of 0 to 1. An HCT‐CI score ≥ 3 was marginally significantly associated with an increased risk of all‐cause death (HR 1.60; 95% CI 0.96‐2.68; P = .07). ACE‐27 captured a greater spectrum of cardiovascular and venous thrombotic disease. No impact of comorbidities on leukemic transformation was observed. Conclusions Although the presence of severe comorbidities was lower when assessed by ACE‐27 (13%) compared with HCT‐CI (23%), and the spectrums of comorbidities captured were different, the overall impact of severe comorbidities as assessed by both scales appears to be similar and associated with a survival disadvantage. Micro‐Abstract In a retrospective study of 309 patients with myelofibrosis, severe burden of comorbidities as assessed by the Adult Comorbidity Evaluation 27 (ACE‐27) or Hematopoietic Cell Transplant Comorbidity Index (HCT‐CI) was associated with worse overall survival. ACE‐27 may be preferred for comorbidity assessment in patients with myeloproliferative neoplasm, as it captures cardiovascular and venous thrombosis–related morbidities better than HCT‐CI.