Krina Patel

Phase I study of cord blood‐derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma

Multiple myeloma (MM) is a disease with known immune dysregulation. Natural killer (NK) cells have shown preclinical activity in MM. We conducted a first‐in‐human study of umbilical cord blood‐derived (CB) NK cells for MM patients undergoing high dose chemotherapy and autologous haematopoietic stem cell transplantation (auto‐HCT). Patients received lenalidomide (10 mg) on days −8 to −2, melphalan 200 mg/m2 on day −7, CB‐NK cells on day −5 and auto‐HCT on day 0. Twelve patients were enrolled, three on each of four CB‐NK cell dose levels: 5 × 106, 1 × 107, 5 × 107 and 1 × 108 CB‐NK cells/kg. Ten patients had either high‐risk chromosomal changes or a history of relapsed/progressed disease. There were no infusional toxicities and no graft‐versus‐host disease. One patient failed to engraft due to poor autologous graft quality and was rescued with a back‐up autologous graft. Overall, 10 patients achieved at least a very good partial response as their best response, including eight with near complete response or better. With a median follow‐up of 21 months, four patients have progressed or relapsed, two of whom have died. CB‐NK cells were detected in vivo in six patients, with an activated phenotype (NKG2D+/NKp30+). These data warrant further development of this novel cellular therapy.

Clofarabine Plus Busulfan is an Effective Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Lymphoblastic Leukemia: Long-Term Study Results

We investigated the long-term safety and disease control data obtained with i.v. busulfan (Bu) combined with clofarabine (Clo) in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (HSCT). A total of 107 patients, median age 38 years (range, 19 to 64 years) received a matched sibling donor (n = 52) or matched unrelated donor (n = 55) transplant for ALL in first complete remission (n = 62), second complete remission (n = 28), or more advanced disease (n = 17). Nearly one-half of the patients had a high-risk cytogenetic profile as defined by the presence of t(9;22) (n = 34), t(4;11) (n = 4), or complex cytogenetics (n = 7). Clo 40 mg/m2 was given once daily, with each dose followed by pharmacokinetically dosed Bu infused over 3 hours daily for 4 days, followed by hematopoietic cell infusion after 2 days of rest. The Bu dose was based on the drug clearance as determined by a test Bu dose of 32 mg/m2. The target daily area under the curve was 5500 µmol/min for patients aged <60 years and 4000 µmol/min for patients aged >59 years. With a median follow-up of 3.3 years among surviving patients (range, 1 to 5.8 years), the 2-year progression-free survival (PFS) for patients undergoing HSCT in first complete remission (CR1), second complete remission (CR2), or more advanced disease was 62%, 34%, and 35%, respectively. The regimen was well tolerated, with nonrelapse mortality (NRM) of 10% at 100 days and 31% at 2 years post-HSCT. The incidence of grade II-IV and III-IV acute graft-versus-host disease (GVHD) was 35% and 10%, respectively; 18% patients developed extensive chronic GVHD. The 2-year overall survival (OS) for patients undergoing HSCT in CR1, CR2, or more advanced disease was 70%, 57%, and 35%, respectively. Among 11 patients aged >59 years treated with reduced-dose Bu in CR1 (n = 7) or CR2 (n = 4), 4 remain alive and disease-free, with a median follow-up of 2.6 years (range, 2 to 4.7 years). Only the presence of minimal residual disease at the time of transplantation was associated with significantly worse PFS and OS in multivariate analysis. Our data indicate that the Clo-Bu combination provides effective disease control while maintaining a favorable safety profile. OS and NRM rates compare favorably with those for traditional myeloablative total body irradiation-based conditioning regimens.

High-dose gemcitabine, busulfan, and melphalan for autologous stem-cell transplant in patients with relapsed or refractory myeloma: a phase 2 trial and matched-pair comparison with melphalan

BACKGROUND High-dose melphalan is of little benefit as a regimen for patients with relapsed or refractory myeloma undergoing an autologous stem-cell transplant (ASCT). The poor performance of single-agent melphalan in this setting prompted us to study a new high-dose combination of infused gemcitabine, busulfan, and melphalan. METHODS We did a phase 2 trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). We enrolled patients with primary refractory or relapsed myeloma who had received treatment with bortezomib, an immunomodulatory drug, or both, or who were receiving a salvage ASCT. Gemcitabine was infused at 1875 mg/m2 for 3 h for 2 days, followed by busulfan (target area under the curve 4000 μmol/L per min per day for 4 days) and melphalan (60 mg/m2 per day for 2 days). The primary endpoint of this trial was to establish the proportion of patients with measurable disease at ASCT receiving gemcitabine, busulfan, and melphalan who achieved stringent complete remission in accordance with the International Myeloma Working Group criteria. We then retrospectively compared the patients in this study with all other concurrent patients at the MD Anderson Cancer Center who were eligible for this trial but declined to participate or had no financial coverage for ASCT in a clinical trial and instead received melphalan at 200 mg/m2 intravenously over 30 min on 1 day, followed by ASCT (control group). To compare survival outcomes, we used a statistical algorithm to select a subset of patients from this control cohort who were matched in a 1-2:1 ratio with the patients in the gemcitabine, busulfan, and melphalan group by sex, age, disease status, refractory to both proteasome inhibitors and immunomodulatory imide drugs, time from diagnosis to ASCT, and cytogenetic risk. All analyses were per protocol. This is the final analysis of the clinical trial, which is registered at ClinicalTrials.gov, number NCT01237951. FINDINGS Between Nov 30, 2010, and Dec 11, 2013, we enrolled 74 patients into the gemcitabine, busulfan, and melphalan trial. In these patients, median age was 58 years (IQR 51-62), median number of previous lines of therapy was two (2-5), 38 patients had high-risk cytogenetics, 17 were unresponsive to all previous treatments, and 32 were receiving a salvage ASCT. We identified 184 patients for the concurrent control cohort. The study patients and the concurrent controls received similar post-ASCT maintenance. Among patients with measurable disease at ASCT, 16 of 65 patients (24·6%, 95% CI 14·2-35·0) in the gemcitabine, busulfan, and melphalan group had stringent complete remission compared with 22 of 174 patients (12·6%, 10·1-15·1) in the concurrent control group (p=0·040). Median follow-up time was 36 months (IQR 30-46) in the patients receiving gemcitabine, busulfan, and melphalan and 34 months (25-53) in the matched control subset (n=111). With respect to the secondary survival endpoints, the gemcitabine, busulfan, and melphalan cohort had significantly longer median progression-free survival than the matched control cohort (15·1 months [95% CI 8·7-22·1] vs 9·3 months [8·0-10·7]) with a significantly reduced risk of progression or death (HR 0·55, 95% CI 0·38-0·81, log-rank p=0·030), as well as significantly longer median overall survival (37·5 months [26-not reached] vs 23·0 months [16·6-30·5]) and a lower risk of death (HR 0·60, 0·34-0·84, log-rank p=0·0092). For only the patients treated with gemcitabine, busulfan, and melphalan, grade 3 or worse adverse events included grade 3 mucositis (12 patients), grade 3 dermatitis (five patients), grade 3 aminotransferase elevation (seven patients), grade 3 diarrhoea (two patients), and three treatment-related deaths. One death was cardiac sudden death and two were due to sepsis. INTERPRETATION Gemcitabine, busulfan, and melphalan is a comparatively safe and active regimen for ASCT in patients with refractory or relapsed myeloma. Better outcomes were achieved in patients who received this regimen than in a concurrent matched cohort receiving melphalan, although this will need to be confirmed in a prospective, randomised trial. FUNDING Otsuka Pharmaceutical Development & Commercialization and US National Cancer Institute.BACKGROUND High-dose melphalan is of limited benefit as autologous stem-cell transplantation (ASCT) regimen for relapsed/refractory myeloma. Its poor results in this setting prompted us to study a new high-dose combination of infusional gemcitabine/busulfan/melphalan (Gem/Bu/Mel). METHODS We conducted a phase 2 trial of Gem/Bu/Mel in patients with primary refractory or relapsed disease after bortezomib and/or an immunomodulatory drug (IMiD), or receiving a salvage ASCT. Gemcitabine (1,875 mg/m2 over 3 hours × 2 days) was followed by busulfan (target AUC 4,000/day × 4 days) and melphalan (60 mg/m2/day × 2 days). The primary endpoint of this trial was to determine the stringent complete remission (sCR) rate of Gem/Bu/Mel in this population. We then retrospectively compared the study patients with all other concurrent patients eligible for this trial who, instead, received melphalan at 200 mg/m2 IV at our center. For survival outcomes, we used a statistical algorithm to select a subset from the control cohort that matched with the Gem/Bu/Mel patients by gender, age, disease status, double refractoriness to proteasome inhibitors/IMIDs, duration from diagnosis to transplant and cytogenetic risk, in a 1–2:1 ratio. All analyses are per protocol. This is the final analysis of the clinical trial. Trial registered at NCI.gov (NCT01237951). FINDINGS We enrolled 74 patients on the Gem/Bu/Mel trial, median age 58 (interquartile range [IQR], 11), median 2 prior therapy lines (IQR, 3), 38 high-risk cytogenetics, 17 unresponsive to all prior treatments, and 33 receiving a salvage ASCT. Toxicities of Gem/Bu/Mel included grade 3 mucositis (N=12), grade 3 dermatitis (N=5), grade 3 transaminase elevation (N=7), grade 3 diarrhea (N=2), grade 5 sudden death (N=1) and grade 5 sepsis (N=2). The study patients and the 184 concurrent controls received similar post-ASCT maintenance. Gem/Bu/Mel resulted in more sCR (24.6% v 12.6%, P=0.040), similar overall responses (73.8% v 74.1%, P=0.77) and similar transplant-related mortality (4.0% v 3.8%, P=0.90). The median follow-up times for the Gem/Bu/Mel patients and the matched subset (N=111) were 36 months (IQR, 15.2) and 34 months (IQR, 27), respectively. Gem/Bu/Mel resulted in improved progression-free survival (median 15.1 v 9.3 months, P=0.0030; hazard ratio=0.60; P=0.021) and overall survival (median 37.5 v 23 months, P=0.0092; hazard ratio=0.65, P=0.0087). INTERPRETATION Gem/Bu/Mel is a safe and active ASCT regimen for refractory/relapsed myeloma, with better outcomes than a concurrent matched cohort receiving melphalan. Funding Supported by a grant from Otsuka Pharmaceutical Development & Commercialization Inc. and NCI Grant P30 CA016672.

Outcomes in patients with multiple myeloma with TP53 deletion after autologous hematopoietic stem cell transplant.

TP53 gene deletion is associated with poor outcomes in multiple myeloma (MM). We report the outcomes of patients with MM with and without TP53 deletion who underwent immunomodulatory drug (IMiD) and/or proteasome inhibitor (PI) induction followed by autologous hematopoietic stem cell transplant (auto‐HCT). We identified 34 patients with MM and TP53 deletion who underwent IMiD and/or PI induction followed by auto‐HCT at our institution during 2008–2014. We compared their outcomes with those of control patients (n = 111) with MM without TP53 deletion. Median age at auto‐HCT was 59 years in the TP53‐deletion group and 58 years in the control group (P = 0.4). Twenty‐one patients (62%) with TP53 deletion and 69 controls (62%) achieved at least partial remission before auto‐HCT (P = 0.97). Twenty‐three patients (68%) with TP53 deletion and 47 controls (42%) had relapsed disease at auto‐HCT (P = 0.01). Median progression‐free survival was 8 months for patients with TP53 deletion and 28 months for controls (P < 0.001). Median overall survival was 21 months for patients with TP53 deletion and 56 months for controls (P < 0.001). On multivariate analysis of both groups, TP53 deletion (hazard ratio 3.4, 95% confidence interval 1.9–5.8, P < 0.001) and relapsed disease at auto‐HCT (hazard ratio 2.0, 95% confidence interval 1.2–3.4, P = 0.008) were associated with a higher risk of earlier progression. In MM patients treated with PI and/or IMiD drugs, and auto‐HCT, TP53 deletion and relapsed disease at the time of auto‐HCT are independent predictors of progression. Novel approaches should be evaluated in this high‐risk population. Am. J. Hematol. 91:E442–E447, 2016.

Doxorubicin-Based Chemotherapy and Radiation Therapy Produces Favorable Outcomes in Limited-Stage Plasmablastic Lymphoma: A Single-Institution Review

BACKGROUND Plasmablastic lymphoma (PBL) is an aggressive variant of diffuse large B-cell lymphoma. We sought to assess the treatment outcomes after combined-modality therapy for early-stage PBL. MATERIALS AND METHODS We retrospectively reviewed the outcomes of 10 consecutive patients diagnosed with stage I-II PBL from February 2001 to December 2013 at a single institution. The baseline clinical characteristics, treatment modalities, overall outcomes, and treatment-related toxicity were assessed. RESULTS The median age at diagnosis was 50.5 years. All patients had extranodal disease; 2 were positive for human immunodeficiency virus. Seven patients received hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone)-based chemotherapy, 2 received CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), and 1 received dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin). Radiotherapy (RT) was administered after a complete response to chemotherapy in 7 patients and a partial response in 1 patient. At a median follow-up period of 42 months, the estimated 2-year progression-free and overall survival rates were 90% and 100%, respectively. CONCLUSION PBL can be successfully treated with aggressive chemotherapy followed by RT. The treatment was well tolerated and can result in long-term survival for patients with limited-stage disease.

Outcome of Patients with Multiple Myeloma and CKS1B Gene Amplification after Autologous Hematopoietic Stem Cell Transplantation

The gain/amplification of the CKS1B gene on chromosome 1q21 region is associated with a poor outcome in patients with multiple myeloma (MM). However, there are limited data on the outcome of patients with CKS1B amplification after a single high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT). We retrospectively evaluated the outcome of patients with CKS1B amplification who received an auto-HCT between June 2012 and July 2014 at our institution. We identified 58 patients with MM and CKS1B gene amplification detected by fluorescent in situ hybridization (FISH). We compared their outcomes with a propensity score-matched control group of 58 patients without CKS1B amplification who were treated at approximately the same time. The primary objective was to compare the progression-free (PFS) and overall survival (OS) between the CKS1B and the control groups. Stratified log-rank test with the matched pairs as strata and double robust estimation under the Cox model were used to assess the effect of CKS1B gene amplification on PFS or OS in the matched cohort. Patients in the CKS1B and control groups were well matched for age, gender, disease status, year of auto-HCT, response to pretransplantation therapy, and baseline hemoglobin level. In both groups, 57% patients were in first remission and 43% had relapsed disease at auto-HCT. Twenty-seven (47%) patients with CKS1B amplification had concurrent monosomy 13 or 13q deletion; 6 (10%) by conventional cytogenetics only, 16 (28%) by FISH only, and 5 (9%) by both. Median follow-up after auto-HCT was 25.4 months. The median PFS of the CKS1B and the control groups were 15.0 months and 33.0 months (P = .002), respectively. The median OS have not been reached yet. The 2-year OS rates in the CKS1B and the control groups were 62% and 91% (P = .02), respectively. In conclusion, Patients with CKS1B amplification are more likely to have additional high-risk cytogenetic abnormalities and a shorter PFS and OS after an auto-HCT.

Outcome of autologous hematopoietic stem cell transplantation in refractory multiple myeloma

Despite the introduction of effective, novel agents, the outcome of patients with refractory multiple myeloma remains poor, particularly those who are refractory to both proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs). Limited data are available on the role of autologous hematopoietic stem cell transplantation in this population.

Successful treatment of aplastic anemia-paroxysmal nocturnal hemoglobinuria associated with eosinophilic fasciitis with matched unrelated donor allogeneic peripheral blood stem cell transplantation.

We report the first patient case of successful treatment intervention for both eosinophilic fasciitis and aplastic anemia with allogeneic peripheral blood stem cell transplantation from a matched unrelated donor after multiple immunosuppressant failure.

Bendamustine added to allogeneic conditioning improves long-term outcomes in patients with CLL

Bendamustine has shown a favorable safety profile when included in chemotherapy regimens for several types of lymphoma, including CLL. This study investigated the long-term effect of adding bendamustine to a conditioning regimen on survival, rate of engraftment, immune recovery and GvHD after allogeneic stem cell transplantation (alloSCT) in CLL patients. These outcomes were compared with the fludarabine, cyclophosphamide and rituximab (FCR) conditioning regimen. We reviewed the data for 89 CLL patients treated on three trials at our institution. Twenty-six (29%) patients received bendamustine, fludarabine and rituximab (BFR) and 63 (71%) received FCR. Patient characteristics were similar in both groups. Ten (38%) BFR-treated patients vs only two (3%) FCR-treated patients did not experience severe neutropenia (P=<0.001). The 3-year overall survival estimates for the BFR and FCR groups were 82 and 51% (P=0.03), and the 3-year PFS estimates were 63% and 27% (P=0.001), respectively. The 2-year treatment-related mortality was 8 and 23% and the incidence of grade 3 or 4 GvHD was 4% and 10%, respectively. This study is the first to report that addition of bendamustine to alloSCT conditioning for CLL patients is associated with improved survival and lower mortality, myelosuppression, and GvHD.

Feasibility of Lenalidomide Therapy for Persistent Chronic Lymphocytic Leukemia after Allogeneic Transplantation

In patients with chronic lymphocytic leukemia (CLL), persistence of disease after allogeneic stem cell transplantation (alloSCT) can result in poor outcomes. In an effort to improve these outcomes, patients with persistent CLL who were 90 to 100 days beyond alloSCT with no evidence of graft-versus-host-disease (GVHD) were randomized to receive lenalidomide or standard care (withdrawal of immunosuppression followed by donor lymphocyte infusion). Lenalidomide was initiated at 5 mg every other day and increased to 10 mg daily, if tolerated, in each patient. Of 38 patients enrolled, 17 (45%) met the eligibility criteria for randomization. Of these 17 patients, 8 were randomized to undergo lenalidomide therapy. Five (62%) patients had to stop taking the drug because of toxicity. The main reason for drug discontinuation was acute GVHD in 43% of patients. This incidence was 11% in the patients who were randomized to not receive lenalidomide. With a median follow-up of 2.6 years, the median survival was 3.4 years for those receiving lenalidomide. This was not reached in patients randomized to not receive lenalidomide and in patients in complete remission who were not randomized. These results suggested that treatments other than lenalidomide are needed for persistent CLL after alloSCT.