Venetoclax sensitivity in multiple myeloma is associated with B-cell gene expression.

Venetoclax is a highly potent, selective BCL2 inhibitor capable of inducing apoptosis in cells dependent on BCL2 for survival. Most myeloma is MCL1-dependent; however, a subset of myeloma enriched for translocation t(11;14) is codependent on BCL2 and thus sensitive to venetoclax. The biology underlying this heterogeneity remains poorly understood. We show that knockdown of cyclin D1 does not induce resistance to venetoclax, arguing against a direct role for cyclin D1 in venetoclax sensitivity. To identify other factors contributing to venetoclax response, we studied a panel of 31 myeloma cell lines and 25 patient samples tested for venetoclax sensitivity. In cell lines, we corroborated our previous observation that BIM binding to BCL2 correlates with venetoclax response and further showed that knockout of BIM results in decreased venetoclax sensitivity. RNA-sequencing analysis identified expression of B-cell genes as enriched in venetoclax-sensitive myeloma, although no single gene consistently delineated sensitive and resistant cells. However, a panel of cell surface makers correlated well with ex vivo prediction of venetoclax response in 21 patient samples and may serve as a biomarker independent of t(11;14). Assay for transposase-accessible chromatin sequencing of myeloma cell lines also identified an epigenetic program in venetoclax-sensitive cells that was more similar to B cells than that of venetoclax-resistant cells, as well as enrichment for basic leucine zipper domain-binding motifs such as BATF. Together, these data indicate that remnants of B-cell biology are associated with BCL2 dependency and point to novel biomarkers of venetoclax-sensitive myeloma independent of t(11;14).

Final results of a phase 1 study of loncastuximab tesirine in relapsed/refractory B-cell non-Hodgkin lymphoma.

The prognosis for patients with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) remains poor, with a need for alternatives to current salvage therapies. Loncastuximab tesirine (ADCT-402) is an antibody-drug conjugate comprising a humanized anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer toxin. Presented here are final results of a phase 1 dose-escalation and dose-expansion study in patients with R/R B-NHL. Objectives were to determine the maximum tolerated dose (MTD) and recommended dose(s) for expansion and evaluate safety, clinical activity, pharmacokinetics, and immunogenicity of loncastuximab tesirine. Overall, 183 patients received loncastuximab tesirine, with 3 + 3 dose escalation at 15 to 200 µg/kg and dose expansion at 120 and 150 µg/kg. Dose-limiting toxicities (all hematologic) were reported in 4 patients. The MTD was not reached, although cumulative toxicity was higher at 200 µg/kg. Hematologic treatment-emergent adverse events were most common, followed by fatigue, nausea, edema, and liver enzyme abnormalities. Overall response rate (ORR) in evaluable patients was 45.6%, including 26.7% complete responses (CRs). ORRs in patients with diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, and follicular lymphoma were 42.3%, 46.7%, and 78.6%, respectively. Median duration of response in all patients was 5.4 months and not reached in patients with DLBCL (doses ≥120 µg/kg) who achieved a CR. Loncastuximab tesirine had good stability in serum, notable antitumor activity, and an acceptable safety profile, warranting continued study in B-NHL. The recommended dose for phase 2 was determined as 150 µg/kg every 3 weeks for 2 doses followed by 75 µg/kg every 3 weeks. This trial was registered at www.clinicaltrials.gov as #NCT02669017.

Plain Language Summary of the iNNOVATE study: ibrutinib plus rituximab is well-tolerated and effective in people with Waldenström's macroglobulinemia.

WHAT IS THIS SUMMARY ABOUT?: This article provides a short summary of 5-year results from the iNNOVATE trial. The original paper was published in the Journal of Clinical Oncology in October 2021. People with Waldenström's macroglobulinemia (WM) were randomly divided into two groups of 75 people each. One group received a combination treatment composed of two drugs, ibrutinib plus rituximab, and the other group took placebo ("sugar pill") plus rituximab. Ibrutinib (also known by the brand name Imbruvica®) is a drug that reduces cancer cells' ability to multiply and survive. Ibrutinib is an FDA-approved drug for the treatment of WM. Rituximab is a drug that helps the immune system find and kill cancer cells. Participants in the trial were treated and their health monitored for up to 5 years (63 months). WHAT WERE THE RESULTS?: During the 5 years of monitoring, more people who took ibrutinib plus rituximab experienced an improvement in their disease and lived longer without their disease getting worse compared to those who took placebo plus rituximab. Side effects from ibrutinib and rituximab were manageable and generally decreased over time. Participants in both study groups reported improvements in quality of life, but those who took ibrutinib plus rituximab reported significantly greater improvement in their quality of life (as measured by FACT-An score) compared to those who took placebo plus rituximab. WHAT DO THE RESULTS MEAN?: These results show that ibrutinib plus rituximab is better than rituximab alone in people with WM and that ibrutinib plus rituximab is safe and effective in the long term. This information confirms the role of ibrutinib plus rituximab as a standard of care for WM. Clinical Trial Registration: NCT02165397 (ClinicalTrials.gov).

Gemcitabine and bendamustine is a safe and effective salvage regimen for patients with recurrent/refractory Hodgkin lymphoma: Results of a phase 1/2 study.

BACKGROUND: Both gemcitabine and bendamustine have been evaluated in patients with recurrent/refractory Hodgkin lymphoma but to the authors' knowledge not as a doublet. The authors completed a phase 1/2 trial to identify the optimal dose and frequency of administration and to assess the efficacy of this combination in patients with recurrent/refractory Hodgkin lymphoma. METHODS: Patients were treated up to a maximum dose of gemcitabine (1000 mg/m2 on day 1) and bendamustine (120 mg/m2 on days 1 and 2), which was determined to be the recommended phase 2 dose, administered every 21 days for up to 6 cycles. Patients could discontinue study therapy after 2 cycles to proceed with autologous or allogeneic stem cell transplantation. RESULTS: No dose-limiting toxicities were identified, but 4 patients experienced grade 3 to 5 pulmonary adverse events (toxicity was graded according to Common Terminology Criteria for Adverse Events [version 4]). A total of 26 patients were enrolled having completed a median of 4 prior lines of therapy (range, 1-7 lines), including 13 patients at the recommended phase 2 dose, in whom the overall response rate was 69% and the complete response rate was 46%. The median progression-free survival for the phase 2 patients was 11 months (95% CI, 3 months to not reached), and the median overall survival for this group had not been reached at the time of last follow-up (95% CI, 4 months to not reached). CONCLUSIONS: This doublet was found to be tolerable and effective, but patients must be monitored closely for pulmonary toxicity. The authors currently are evaluating this doublet in combination with nivolumab.

Clinical efficacy of daratumumab, pomalidomide, and dexamethasone in patients with relapsed or refractory myeloma: Utility of re-treatment with daratumumab among refractory patients.

BACKGROUND: The efficacy of daratumumab (DARA) both as a monotherapy and in combination with standard-of-care regimens in multiple myeloma (MM) has been established in clinical trials. This article presents a retrospective analysis of the safety and efficacy of DARA in combination with pomalidomide (POM) and dexamethasone (ie, daratumumab, pomalidomide, and dexamethasone [DARA-POM-D]) and, more importantly, the long-term follow-up of a cohort that was naive to DARA and POM as well as a cohort in which the utility of re-treatment was evaluated among patients who were DARA- and/or POM-refractory. METHODS: Thirty-four consecutive patients with relapsed and/or refractory MM treated with DARA-POM-D at the Winship Cancer Institute of Emory University from January 2015 through July 2016 were included in the analysis. The study was approved by Emory University's institutional review board. All received prior proteasome inhibitors and immunomodulatory drugs (IMiDs) and were refractory to their last line of therapy. RESULTS: All patients were lenalidomide-refractory, and 91% were bortezomib-refractory. Two cohorts were identified on the basis of prior exposure to DARA and/or POM. Cohort 1 (12 patients) was DARA- and POM-naive, and cohort 2 (22 patients) was DARA- and/or POM-refractory. A subgroup of 12 patients in cohort 2 (cohort 3) was DARA- and POM-refractory. The combination's tolerability was consistent with the results of the published phase 1b study (EQUULES) that evaluated the combination and no new safety signals were observed. The overall response rates (ORRs) were 91.7%, 40.9%, and 33.3% in cohorts 1, 2, and 3, respectively. Deep responses, including 4 stringent complete responses, were observed in cohort 1. In cohort 2, the ORR comprised 8 partial responses (PRs) and 1 very good PR. The median progression-free survival (PFS) was not reached in cohort 1 at a median follow-up of 41 months, and it was 3.2 months in cohort 2. DARA-POM-D not only was effective in DARA- and POM-naive patients but also produced clinical responses in a third of patients re-treated with these drugs. CONCLUSIONS: A better than quadrupled PFS benefit observed in cohort 1 in comparison with the previously reported benefit in the EQUULEUS trial (which led to US Food and Drug Administration approval of the DARA-POM-D combination) highlights the fact that the introduction of monoclonal antibody combination strategies and IMiDs as earlier lines of therapeutic options potentially could deliver better clinical outcomes. One-third of patients refractory to separate lines of DARA and/or POM responded when they were re-treated with a combination, and this resulted in survival benefits equivalent to those of other antimyeloma agents/combinations available for DARA-refractory patients.

Survival outcomes of patients with primary plasma cell leukemia (pPCL) treated with novel agents.

BACKGROUND: Primary plasma cell leukemia (pPCL) is an aggressive plasma cell disorder characterized by circulating plasma cells and a poor prognosis. Although patients who have pPCL benefit from the use of stem cell transplantation (SCT) and novel agents, their prognosis remains inferior to that of patients who have myeloma. METHODS: This was a retrospective analysis of 38 consecutive patients with pPCL who were diagnosed between October 2005 and July 2016 and were registered in the Winship Cancer Institute of Emory University database. Baseline characteristics as well as data about treatment and survival outcomes were collected. RESULTS: The median patient age at diagnosis was 58 years. All patients received a bortezomib-based induction regimen, and 92% received both bortezomib and an immunomodulatory drug (thalidomide or lenalidomide); in addition, 74% of patients underwent autologous SCT (ASCT), and 61% received maintenance therapy. The best response to first-line therapy was a partial response or better in 87% of patients, and 45% had a complete response (CR). The achievement of ≥CR was a predictor for prolonged progression-free survival (PFS) and overall survival (OS). The median PFS was 20 months, and the median OS was 33 months. PFS was prolonged in patients who underwent ASCT compared with those who did not undergo ASCT (25 vs 6 months; P = .004), and patients who received maintenance therapy after ASCT had prolonged median PFS (27 vs 11 months; P = .03) and a trend toward prolonged OS (median, 38 vs 22 months; P = .06) compared with those who did not receive maintenance therapy. CONCLUSIONS: The current data support the use of regimens combining novel agents in the upfront treatment of patients with pPCL as well as the role of ASCT and maintenance therapy for long-term disease control.

Safety and survival outcomes for bloodless transplantation in patients with myeloma.

High-dose therapy (HDT) and autologous stem cell transplantation (ASCT) are established components in the treatment of multiple myeloma; however, undergoing transplantation usually requires hematopoietic support, which poses a challenge among patients who are unwilling to receive blood products. Most transplant centers decline HDT/ASCT to these patients because of safety concerns. Here, the authors' institutional data on safety, engraftment parameters, and survival outcomes after bloodless ASCT (BL-ASCT) are examined among patients with myeloma. This retrospective case-control study included patients who underwent BL-ASCT and Transfusion-supported ASCT (TS-ASCT) at Emory University Hospital between August 2006 and August 2016. In total, 24 patients who underwent BL-ASCT and 70 who underwent TS-ASCT were included. The median time for neutrophil engraftment, platelet engraftment and the median length of hospital stay all were equivalent for both groups. There were no transplant-related cardiovascular complications or mortality in either the BL-ASCT group or the TS-ASCT group. The median progression-free survival was 36 months and 44 months in the BL-ASCT and TS-ASCT groups, respectively (P = .277), and the median OS was not reached in either group at a median follow-up of 59 months after ASCT (P = .627). There was no transplant-related mortality at the 100-day or 1-year mark in either group. BL-ASCT is safe and feasible; transplant-related mortality, cardiovascular and hematologic complications are similar to those associated with TS-ASCT. Furthermore, BL-ASCT can yield similar engraftment and survival parameters comparable to those observed with TS-ASCT.

Ibrutinib for patients with rituximab-refractory Waldenström's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial.

BACKGROUND: In the era of widespread rituximab use for Waldenström's macroglobulinaemia, new treatment options for patients with rituximab-refractory disease are an important clinical need. Ibrutinib has induced durable responses in previously treated patients with Waldenström's macroglobulinaemia. We assessed the efficacy and safety of ibrutinib in a population with rituximab-refractory disease. METHODS: This multicentre, open-label substudy was done at 19 sites in seven countries in adults aged 18 years and older with confirmed Waldenström's macroglobulinaemia, refractory to rituximab and requiring treatment. Disease refractory to the last rituximab-containing therapy was defined as either relapse less than 12 months since last dose of rituximab or failure to achieve at least a minor response. Key exclusion criteria included: CNS involvement, a stroke or intracranial haemorrhage less than 12 months before enrolment, clinically significant cardiovascular disease, hepatitis B or hepatitis C viral infection, and a known bleeding disorder. Patients received oral ibrutinib 420 mg once daily until progression or unacceptable toxicity. The substudy was not prospectively powered for statistical comparisons, and as such, all the analyses are descriptive in nature. This study objectives were the proportion of patients with an overall response, progression-free survival, overall survival, haematological improvement measured by haemoglobin, time to next treatment, and patient-reported outcomes according to the Functional Assessment of Cancer Therapy-Anemia (FACT-An) and the Euro Qol 5 Dimension Questionnaire (EQ-5D-5L). All analyses were per protocol. The study is registered at ClinicalTrials.gov, number NCT02165397, and follow-up is ongoing but enrolment is complete. FINDINGS: Between Aug 18, 2014, and Feb 18, 2015, 31 patients were enrolled. Median age was 67 years (IQR 58-74); 13 (42%) of 31 patients had high-risk disease per the International Prognostic Scoring System Waldenström Macroglobulinaemia, median number of previous therapies was four (IQR 2-6), and all were rituximab-refractory. At a median follow-up of 18·1 months (IQR 17·5-18·9), the proportion of patients with an overall response was 28 [90%] of 31 (22 [71%] of patients had a major response), the estimated 18 month progression-free survival rate was 86% (95% CI 66-94), and the estimated 18 month overall survival rate was 97% (95% CI 79-100). Baseline median haemoglobin of 10·3 g/dL (IQR 9·3-11·7) increased to 11·4 g/dL (10·9-12·4) after 4 weeks of ibrutinib treatment and reached 12·7 g/dL (11·8-13·4) at week 49. A clinically meaningful improvement from baseline in FACT-An score, anaemia subscale score, and the EQ-5D-5L were reported at all post-baseline visits. Time to next treatment will be presented at a later date. Common grade 3 or worse adverse events included neutropenia in four patients (13%), hypertension in three patients (10%), and anaemia, thrombocytopenia, and diarrhoea in two patients each (6%). Serious adverse events occurred in ten patients (32%) and were most often infections. Five (16%) patients discontinued ibrutinib: three due to progression and two due to adverse events, while the remaining 26 [84%] of patients are continuing ibrutinib at the time of this report. INTERPRETATION: The sustained responses and median progression-free survival time, combined with a manageable toxicity profile observed with single-agent ibrutinib indicate that this chemotherapy-free approach is a potential new treatment choice for patients who had heavily pretreated, rituximab-refractory Waldenström's macroglobulinaemia. FUNDING: Pharmacyclics LLC, an AbbVie Company.

Does the frequency of molecular monitoring after tyrosine kinase inhibitor discontinuation affect outcomes of patients with chronic myeloid leukemia?

BACKGROUND: To the authors' knowledge, the optimal frequency of monitoring after tyrosine kinase inhibitor (TKI) discontinuation in patients with chronic myeloid leukemia (CML) has not been established. Data regarding the discontinuation of second-generation TKIs used in first-line treatment or after the failure of first-line treatment with TKIs are limited. Herein, the authors report real-world experience with "reduced frequency" molecular monitoring in patients with CML in all phases who discontinued treatment with imatinib, dasatinib, or bosutinib. METHODS: The records of patients who discontinued TKIs were reviewed. Patients who discontinued TKIs were monitored prospectively on an intended schedule of monthly blood quantitative reverse transcriptase-polymerase chain reaction for BCR-ABL1 for 3 months, quarterly for 12 months, and every 6 months thereafter until loss of major molecular response (MMR). After loss of MMR, the TKI that previously was discontinued was reinitiated. RESULTS: Between January 2010 and September 2015, a total of 24 patients in chronic (21 patients), accelerated (2 patients), and lymphoid blast (1 patient) phase discontinued imatinib (16 patients), dasatinib (5 patients), or bosutinib (3 patients) used in the front-line treatment or beyond. Blood quantitative reverse transcriptase-polymerase chain reaction for BCR-ABL1 was performed 1.3 ± 0.7 times within the first 3 months (24 patients) and 2.7 ± 1.4 times in the following 12 months (18 patients). With a median follow-up of 36.5 months (range, 3.2-67.4 months), the probabilities of treatment-free remission at 1 year and 2 years were 65.7% (95% confidence interval, 55.8%-75.6%) and 59.7% (95% confidence interval, 49.1%-70.3%), respectively. Loss of MMR was observed in 9 patients at a median of 2.8 months (range, 1.8-14.2 months) after discontinuation of TKIs. CONCLUSIONS: With the limitations of a small sample size, the results of the current study demonstrate that less frequent monitoring of BCR-ABL1 does not appear to affect outcomes, and that discontinuation of TKIs used as first-line treatment or beyond after resistance or intolerance to first-line treatment appears feasible. Cancer 2017;123:2482-88. © 2017 American Cancer Society.

Predicting early blast transformation in chronic-phase chronic myeloid leukemia: is immunophenotyping the missing link?

BACKGROUND: Flow cytometry (FC) is a commonly requested test in the workup of leukocytosis in community practices. The role of FC in chronic-phase chronic myeloid leukemia (CP-CML) is unknown. We hypothesized that finding aberrant cells with FC in CP-CML may predict early blast-phase (BP) transformation. METHODS: Results for FC performed at the time of diagnosis for adult and pediatric patients with CP-CML who were referred to our institution were reviewed, and they were correlated with outcomes. RESULTS: FC was performed at the time of diagnosis for 110 of 233 patients (47%) with CP-CML. Aberrant populations, representing a median of 2% (range, 0.3%-15%), were detected with FC in 30% of patients (33 of 110): 2 of these 33 patients expressed lymphoid markers, and 31 expressed aberrant myeloid markers. Patients received imatinib (85%), dasatinib (12%), or nilotinib (3%) as their first-line treatment. With a median follow-up of 43 months (range, 2-113 months), chronic myeloid leukemia transformed to BP in 5 of the 33 patients. The 2 patients with lymphoid markers and the 3 of 31 patients with aberrant myeloid markers experienced a transformation to lymphoid BP at a median of 11 months (range, 4-72 months) after the initiation of tyrosine kinase inhibitor therapy. Although both cases with detectable lymphoid markers rapidly progressed to lymphoid BP, the positive predictive value of BP transformation by the detection of myeloid aberrant cells with FC was only 10% (3 of 31). CONCLUSIONS: In contrast to aberrant myeloid markers, the detection of lymphoid markers by FC at the time of the diagnosis of CP-CML appears to be associated with early progression to lymphoid BP.

Predictors of survival outcomes in phase 1 relapsed or refractory multiple myeloma patients.

BACKGROUND: The categories of the International Myeloma Working Group (IMWG) response criteria for multiple myeloma are based on the magnitude of the change in paraprotein and the normalization of the free light chain ratio (rFLC). However, the relationship between the response by these biomarkers and clinical outcomes has not been validated with novel compounds in the phase 1 setting. Early response predictors may have prognostic value and speed development plans for new agents. METHODS: The relationship between biomarkers of response and clinical outcomes was examined in 87 relapsed or refractory multiple myeloma patients enrolled in nontransplant phase I clinical trials from January 2004 through November 2011 at 4 time landmarks. Progression-free survival (PFS) was the primary outcome, and overall survival (OS) was also assessed. RESULTS: The normalization of rFLC within 4 months predicted improvement in PFS (11.3 vs 2.8 months, P = .038), whereas the normalization of rFLC within 12 months predicted improvement in PFS (6.1 vs 2.8 months, P = .015) and OS (45 vs 17.4 months, P = .002). The magnitude of response in paraprotein predicted and correlated linearly with PFS at all time landmarks (R(2) = 0.703-0.943) when it was assessed with 2 different boundaries. CONCLUSIONS: These findings suggest that the normalization of rFLC and the magnitude of response are viable biomarkers for surrogate endpoints in early-phase clinical trials, validate the use of current IMWG response criteria in the phase 1 setting, and support the use of these biomarkers for drug development endpoints.

A phase II study of bortezomib added to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone in patients with previously untreated indolent non-Hodgkin's lymphoma.

Bortezomib-containing combinations are active in non-Hodgkin lymphoma (NHL) although peripheral neuropathy can limit their dose intensity. Based on our phase I findings, we conducted a phase II trial of bortezomib in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) with a modified dose of vincristine. Patients with untreated indolent NHL received bortezomib (1·6 mg/m(2) ) on days 1 and 8 of a 21-day cycle for up to 8 cycles and R-CHOP with a 1·5 mg cap of vincristine. Patients achieving a complete response (CR) received maintenance rituximab, and remaining patients received maintenance rituximab and bortezomib. The primary endpoint was CR rate; secondary survival analyses were evaluated using the Kaplan-Meier method. Among 29 eligible patients, NHL morphologies included follicular (n = 20), marginal zone (n = 5) and small lymphocytic lymphoma (n = 4). Nineteen patients had CR (66%) and 10 had partial response (34%), yielding a 100% overall response rate. With a median follow-up of 48·7 months, the 4-year progression-free and overall survivals were 83% and 93%. Twenty-two patients experienced peripheral neuropathy of any grade, and two had grade 3 neuropathy. The combination of bortezomib with R-CHOP is effective for indolent NHL, and we plan to evaluate therapies incorporating novel proteasome inhibitors in future studies in NHL.

Incidence and geographic distribution of adult acute leukemia in the state of Georgia.

OBJECTIVE: We investigated an apparent increase in acute lymphoblastic leukemia (ALL) referrals from northern Georgia to a tertiary care center located in Atlanta. METHODS: Cases reported to the Georgia Comprehensive Cancer Registry and the national Surveillance Epidemiology and End Results cancer registry between 1999 and 2008 were analyzed. Age-adjusted incidence rates were calculated for all of the counties and public health regions and were compared with national rates calculated using Surveillance Epidemiology and End Results 17 data. Cases of adult acute myeloid leukemia served as controls. RESULTS: Age-adjusted incidence rates of adult ALL (0.8/100,000) and acute myeloid leukemia (4.6/100,000) were comparable to the national rates (0.9 and 5.2, respectively). The age-adjusted incidence rate of ALL in northern Georgia was 1.1 (95% confidence interval 0.8-1.5) and was not affected by race. CONCLUSIONS: The observed increase in cases of ALL at our tertiary center results from a referral pattern rather than heterogeneous distribution of adult ALL across Georgia.

Treatment of adults with acute lymphoblastic leukemia: do the specifics of the regimen matter?: Results from a prospective randomized trial.

BACKGROUND: Induction therapy for adults with acute lymphoblastic leukemia (ALL) is similar across essentially all regimens, comprised of vincristine, corticosteroids, and anthracyclines intensified with cyclophosphamide, asparaginase, or both. Given the lack of randomized data, to date, no regimen has emerged as standard. The authors previously evaluated cytarabine 3 g/m(2) daily for 5 days with mitoxantrone 80 mg/m(2) (the ALL-2 regimen) as a novel induction regimen. Compared with historic controls, the ALL-2 regimen was superior in terms of incidence of complete remission, failure with resistant disease, and activity in patients with Philadelphia chromosome (Ph)-positive ALL. METHODS: The authors conducted a multicenter, prospective, randomized trial of the ALL-2 regimen compared with a standard 4-drug induction (the L-20 regimen). Patients also received consolidation, maintenance therapy, and central nervous system prophylaxis. The trial accrued patients from August 1996 to October 2004. RESULTS: The median follow-up for survivors was 7 years, and the median patient age was 43 years. Responses were evaluated in 164 patients. The treatment arms were balanced in terms of pretreatment characteristics. The frequency of complete remission for the ALL-2 regimen versus the L-20 regimen was 83% versus 71% (P = .06). More patients on the L-20 arm failed with resistant disease (21% vs 8%; P = .02). Induction deaths were comparable at 9% (ALL-2) versus 7% (L-20). The median survival was similar; and, at 5 years, the survival rate was 33% alive on the ALL-2 arm versus 27% on the L-20. CONCLUSIONS: Despite superior results of induction therapy with the ALL-2 regimen, this treatment did not improve long-term outcomes. When coupled to the reported experience of other studies in adults with ALL, the results of this randomized trial raise the possibility that ultimate outcomes in adult ALL may be independent of the specific regimen chosen. Cancer 2013. © 2012 American Cancer Society.

Epsilon aminocaproic acid prevents bleeding in severely thrombocytopenic patients with hematological malignancies.

BACKGROUND: Despite prophylactic platelet transfusions, bleeding remains a significant problem in thrombocytopenic patients. METHODS: The antifibrinolytic agent epsilon aminocaproic acid (EACA) was administered to 44 chronically (median duration, 273 days) and severely (platelet count, 8 × 10(9)/L; range, 1 × 10(9)/L-19 × 10(9)/L) thrombocytopenic patients with hematological malignancies. Prophylactic EACA at a dose of 1 g twice daily was orally administered for a median duration of 47 days (range, 7 days-209 days) until the platelet count recovered to > 30; × 10(9) /L. Platelets were only transfused if bleeding occurred. RESULTS: While receiving EACA, 59% of the patients did not bleed, 25% had 19 episodes of spontaneously resolving minor bleeding that did not require platelet transfusion, and 16% received a median of 4 platelet transfusions (range, 1 transfusion-8 transfusions) for 1 major traumatic and 9 spontaneous grade 2 to grade 3 bleeding (based on the World Health Organization classification of idiopathic thrombocytopenic purpura). No EACA toxicities were noted, and venous thromboses were not observed. CONCLUSIONS: EACA is well tolerated and is associated with a low risk of major bleeding in patients with hematological malignancies who are experiencing chronic severe thrombocytopenia.

Early clearance of peripheral blood blasts predicts response to induction chemotherapy in acute myeloid leukemia.

BACKGROUND: Early marrow blast clearance 14 days after induction chemotherapy is an independent prognostic indicator of outcomes in acute myeloid leukemia (AML). METHODS: We evaluated the relationship between time to peripheral blood blast clearance after induction and disease status as assessed by day 14 and day 30 marrow biopsies in 162 patients with AML. Day 6 after induction was the optimal cutoff point determined by a receiver operating characteristic analysis and was selected to divide patients into early blast clearance (EBC; ≤6 days; n = 119) and delayed blast clearance (DBC; >6 days; n = 43) groups. RESULTS: DBC patients were older, but otherwise the 2 groups were comparable. Marrow blast clearance on day 14 after induction chemotherapy was observed in 84% of patients in the EBC group and 60% in the DBC group. With a median follow-up of 1538 days, both relapse-free survival (RFS) (442 vs 202 days, P = .0017) and overall survival (OS) (930 vs 429 days, P < .0001) were longer in the EBC group, and a multivariable analysis showed that EBC independently predicted clearance of marrow blasts at day 14 (P = .0018), remission (P = .0179), RFS (P = .0171), and OS (P = .0122). CONCLUSIONS: Early clearance of peripheral blood blasts after induction chemotherapy predicts for early marrow blast clearance, complete remission, RFS, and OS. Cancer 2012.

High-dose cytarabine induction is well tolerated and active in patients with de novo acute myeloid leukemia older than 60 years.

BACKGROUND: High-dose cytarabine (HiDAC) is safe and very effective in younger patients with acute myeloid leukemia (AML), but it generally is not well tolerated in the elderly. METHODS: The authors explored the safety and tolerability of a modified HiDAC induction regimen consisting of 6 daily doses of cytarabine at 2 g/m(2) in combination with 3 daily doses of daunorubicin at 45 mg/m(2) in 59 consecutive patients aged >60 years who had de novo AML diagnosed between July 1996 and February 2005. RESULTS: The median patient age was 68 years (range, 60-86 years). The regimen was well tolerated. Infections were common and occurred in 39% of patients, but cerebellar toxicities occurred in only 7% of patients and were reversible. The day-30 induction-related mortality rate was 10%. Overall, 69% of patients achieved complete remissions (CR), and 80% received up to 3 consolidations with HiDAC. The median follow-up for surviving patients was 53 months (range, 17-114 months). The median overall survival was 15.3 months (range, 1-114 months), and the relapse-free survival was 13.8 months (range, 1-113 months). Survival for patients who achieved CR was 27 months (range, 2-114 months). CONCLUSIONS: The modified HiDAC regimen was well tolerated in patients aged >60 years with AML and was associated with low induction mortality and high rates of CR. Nevertheless, these high remissions still were associated with poor overall outcomes.

A phase 1 dose escalation study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone for untreated follicular lymphoma and other low-grade B-cell lymphomas.

BACKGROUND: Bortezomib has demonstrated efficacy in patients with relapsed B-cell non-Hodgkin lymphoma (NHL) both alone and in combination with other agents; however, limited data exist regarding its toxicity in combination with common frontline therapies for indolent NHL. A phase 1 study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone (R-CHOP) was conducted in patients with untreated follicular lymphoma (FL) and other indolent NHLs. METHODS: Nineteen patients, including 10 patients with FL, were enrolled. The median patient age was 59 years (range, 29-71 years). Seven patients had a FL International Prognostic Index score ≥3. R-CHOP with the vincristine dose capped at 1.5 mg was administered on a 21-day cycle for 6 to 8 cycles, and 1 of 3 dose levels of bortezomib (1.0 mg/m(2) [n = 1], 1.3 mg/m(2) [n = 6], or 1.6 mg/m(2) [n = 12]) was administered on days 1 and 8 of each cycle using a Bayesian algorithm for dose escalation. RESULTS: The maximum tolerated dose (MTD) of bortezomib with modified R-CHOP was reached at 1.6 mg/m(2). Dose-limiting toxicity was observed in 5 patients (1 patient at a bortezomib dose of 1.0 mg/m(2), 1 patient at a bortezomib dose of 1.3 mg/m(2), and 3 patients at a bortezomib dose of 1.6 mg/m(2)). Neuropathy occurred in 16 patients (84%), including 2 patients (11%) who experienced grade 3 sensory neuropathy. Grade 4 hematologic toxicity occurred in 4 patients. Of 19 evaluable patients, 100% responded, and the complete response rate was 68%. At a median follow-up of 32 months, the 3-year progression-free survival rate was 89.5%. CONCLUSIONS: Bortezomib combined with modified R-CHOP produced high response rates without substantial increases in toxicity. A phase 2 study of R-CHOP and bortezomib given at this established MTD is currently ongoing.

Characteristics and outcomes of diffuse large B-cell lymphoma presenting in leukaemic phase.

Diffuse large B-cell lymphoma (DLBCL) occasionally presents with circulating malignant cells. The clinical characteristics and long-term outcomes of these patients have not been described. Twenty-nine newly diagnosed DLBCL presenting in leukaemic phase were identified between 1996 and 2010, at two institutions. Median age was 48 years, and patients presented with leucocytosis, high lactate dehydrogenase levels, B symptoms, and high International Prognostic Index score. Extra nodal site involvement was observed in all patients and affected the bone marrow (100%), spleen (62%), pleura/lung (41%), liver (21%), bone (17%), bowels (7%) and cerebrospinal fluid (14%). Blood lymphomatous cells co-expressed CD19, CD20, CD22, CD38, CD45, HLA-DR and FMC7 in >90%, and kappa or lambda light chain restriction in >50%. Ninety per cent received rituximab and anthracycline-based chemotherapy. Overall, remission was complete in 54% and partial in 31%; 15% had resistant disease. Median follow-up was 47 months; 13 (45%) patients remain alive in complete remission. Median progression-free and overall survivals were 11·5 and 46·7 months, respectively. In summary, patients with DLBCL in leukaemic phase present with high tumour burden and frequent involvement of extra nodal sites. In this uncommon DLBCL subgroup, anthracycline-based regimens with rituximab are associated with early morbidity and mortality, but yield approximately 50% 4-year survival.