hyper-CVAD Regimen Research Articles

Monoclonal antibodies: new chance in the management of B-cell acute lymphoblastic leukemia

ABSTRACT Objectives This review aims to see the progress of several clinically-used monoclonal antibodies in treating ALL patients and how they improved patients' outcomes. Methods We searched Web of Science, Elsevier and PubMed for relevant published studies, and summarized eligible evidence on the management of newly-diagnosed and relapsed or refractory ALL with monoclonal antibodies. Ongoing trials were identified from ClinicalTrials.gov. Results Rituximab, an anti-CD20 monoclonal antibody, prolonged patients' complete remission duration and overall survival when combined with hyper-CVAD regimen. Another anti-CD20 monoclonal antibody, Ofatumumab, was reported to have similar benefits. Blinatumomab allows endogenous CD3-positive cytotoxic T cells to target and eliminate CD19-positive blasts. FDA has approved its efficacy in patients with R/R B-ALL and eliminating minimal residual disease (MRD). It serves as a bridge to eradicate MRD before transplantation, and may also be a new choice for patients unable to undergo transplantation. An anti-CD22 monoclonal antibody named Inotuzumab Ozogamicin showed great improvement in patients' outcome, but its toxicity to liver is also worthy of our attention. Conclusion Monoclonal antibodies are proven to be a promising immunotherapeutic strategy to improve ALL patients' outcome in the long term. There's still a need for individualized treatment with effective and well-tolerated medicines. Trial registration: ClinicalTrials.gov identifier: NCT01363128. Trial registration: ClinicalTrials.gov identifier: NCT01466179. Trial registration: ClinicalTrials.gov identifier: NCT02013167. Trial registration: ClinicalTrials.gov identifier: NCT02000427. Trial registration: ClinicalTrials.gov identifier: NCT01564784. Trial registration: ClinicalTrials.gov identifier: NCT03677596. Trial registration: ClinicalTrials.gov identifier: NCT01363297. Trial registration: ClinicalTrials.gov identifier: NCT02981628. Trial registration: ClinicalTrials.gov identifier: NCT03094611. Trial registration: ClinicalTrials.gov identifier: NCT01371630. Trial registration: ClinicalTrials.gov identifier: NCT04224571. Trial registration: ClinicalTrials.gov identifier: NCT02458014. Trial registration: ClinicalTrials.gov identifier: NCT04546399. Trial registration: ClinicalTrials.gov identifier: NCT02879695. Trial registration: ClinicalTrials.gov identifier: NCT03913559. Trial registration: ClinicalTrials.gov identifier: NCT03441061. Trial registration: ClinicalTrials.gov identifier: NCT03739814. Trial registration: ClinicalTrials.gov identifier: NCT02877303. Trial registration: ClinicalTrials.gov identifier: NCT03698552. Trial registration: ClinicalTrials.gov identifier: NCT04601584. Trial registration: ClinicalTrials.gov identifier: NCT04684147. Trial registration: ClinicalTrials.gov identifier: NCT04681105.

Acute Lymphoblastic Leukemia

Acute Lymphoblastic Leukemia

SUPERIOR VENA CAVA SYNDROME SECONDARY TO ADULT T-CELL LYMPHOBLASTIC LYMPHOMA

Superior vena cave (SVC) obstruction can be a substantial contributor to morbidity and mortality in cancer and non-cancer patients. It is currently known to be almost exclusively secondary to malignancy, most frequently lung cancer. A case of SVC syndrome presenting with worsening right-sided chest pain, shortness of breath, facial swelling, neck distension, and cough developing over a period of 12 days is reported. The approach to diagnosis included imaging studies and tissue diagnosis. CT scan of the chest revealed a large right pericardial mass, hilar infrahilar adenopathy, moderate increased right base posterior effusion, and compressive atelectasis. A mediastinal lymph node CT guided core biopsy subsequently revealed adult T-cell lymphoblastic lymphoma. Due to rapid symptom progression, the patient was started on hyper-CVAD regimen and tumor lysis prophylaxis. The etiology, diagnosis, and treatment modalities of the SVC syndrome are discussed further in detail. Given the wide range of symptom severity, identifying and treating severe SVC syndrome promptly can be critical to patient outcomes.

Outcome of young adult patients with very-high-risk acute lymphoblastic leukemia treated with pediatric-type chemotherapy – a single institute experience

Adult patients of acute lymphoblastic leukemia (ALL) with very high-risk (VHR) characteristics have an inferior outcome, and allogeneic hematopoietic stem cell transplantation (HSCT) is usually performed. In contrast, VHR pediatric patients can be treated effectively with minimal residual disease (MRD)-guided pediatric protocols and HSCT are not always needed. We retrospectively reviewed young adult ALL VHR patients treated with the pediatric-type (TPOG-ALL-2002 VHR) regimen in our institute from 2008 to 2019 and compared the event-free survival (EFS) with patients treated with an adult-type regimen (Hyper-CVAD alternating with high dose methotrexate and cytarabine). We identified 16 patients treated with the TPOG and 11 treated with the Hyper-CVAD regimen. Philadelphia chromosome-positive (n=10) and T-cell immunophenotype (n=11) are the most common VHR features. Compared with the Hyper-CVAD group, patients treated with the TPOG regimen showed a trend toward better EFS with a hazard ratio (HR) of 0.42 (p=0.16). Compared with untransplanted patients, HSCT showed a positive trend in the Hyper-CVAD (HR 0.22, p=0.12) but not in the TPOG group (p=0.37). Untransplanted patients treated initially with the hyper-CVAD regimen had a significantly worse outcome than the TPOG regimen (HR 4.19, p<0.05). In the TPOG group, patients with negative MRD at the end of consolidation had a significantly better outcome (HR 0.12, p=0.03). Young adult VHR patients can be effectively treated with the TPOG-ALL-2002 protocol, and those who achieved MRD negativity before the end of consolidation have a good outcome without allogeneic HSCT.

Pediatric-Inspired Protocol Improved Overall Survival in Young Adult Aged 18-30 Years Old with Philadelphia-Negative Acute Lymphoblastic Leukemia Compared to the Standard Adult Hypercvad Protocol

Background:Pediatric acute lymphoblastic leukemia (ALL) have excellent overall survival (OS) compared to adult ALL even in the young adult group. The difference in OS was thought to be due to the difference in treatment protocol with the pediatric-inspired protocol being more intensive and with minimal residual disease (MRD) driven. Strong data has emerged over the past decade from different ALL study groups from Europe and North America to support the use of pediatric-inspired protocol for young adult up to age 30-40 years.HyperCVAD protocol, designed by MD Anderson group in early 90s, has been our standard treatment for adult ALL including young adult since year 2000. Over the past decade, a locally designed pediatric-inspired and MRD driven protocol - known as MASPORE Protocol was used with increasing frequency for those age 30 years and below. MASPORE protocol has higher cumulative dose of vincristine and methotrexate, and use of L-Asparaginase compared to HyperCVAD.In this retrospective study, we aimed to evaluate the safety, tolerability and efficacy of MASPORE protocol in relation to the standard adult ALL protocol - HyperCVAD in young adult aged 18-30 years who were diagnosed with Philadelphia-negative (Ph-) ALL.Method:Patients aged 18 to 30 years old with Ph- ALL who had received HyperCVAD or MASPORE regimen were retrospectively identified via our institution database. Clinical data, toxicity profile, and treatment outcome were collected, compared and analyzed.High risk disease was defined as high white blood cell (WBC) (>30x109/L for B-ALL, and >100x109/L for T-ALL), failure to achieve complete remission (CR) after induction, failure to achieve MRD target at 4 weeks and 8 weeks (in MASPORE group), hypodiploidy, t(9;22), t(4;11) and other MLL-gene rearrangement. An intensified chemotherapy regimen would be given to those high-risk disease in MASPORE regimen, while HyperCVAD regimen has a fixed intensity irrespective of risk.Results:A total of 30 consecutive Ph- ALL patients aged between 18 to 30 years old who were treated with HyperCVAD or MASPORE protocol were included in the analysis. 16 were treated with MASPORE protocol while 14 were treated with HyperCVAD protocol. The median age was 22 years old (Range: 18 - 29 years old). Median follow-up for MASPORE was 37.0 months and HyperCVAD was 85.0 months. HyperCVAD-treated patients were mainly from year 2004 to 2011, while more than 80% of MASPORE patients were treated after year 2013.18 patients had B-ALL, 11 with T-ALL and 1 with mixed phenotypes. 2 patients (1 in each group) had high cytogenetic risk. Median WBC was 14.1 (range: 1.9-287) and 10.1 (range: 1.2-242) for HyperCVAD and MASPORE respectively.All patients achieved CR at the end of induction with no early death (within 60 days of induction). Overall relapse rate was 33.3% with lower relapse rate observed in in MASPORE (18.8%) compared to 50.0% in HyperCVAD. (p-value: 0.07). 4 in HyperCVAD and 3 in MASPORE received allo-SCT subsequently.Median OS in MASPORE was not reached. Median OS for HyperCVAD was 26.3 months (95% CI: 3.6-49.1 months). Overall survival at 3 years were 84.0% and 46.2% in the MASPORE and HyperCVAD, respectively, p=0.038 (Figure 1).Median Leukemia Free Survival (LFS) in MASPORE was not reached. Median LFS in HyperCVAD was 12.5 months (95% CI: 4.2-20.8 months). LFS at 3 years were 75.8% and 38.5% in the MASPORE and HyperCVAD respectively, p=0.089 (Figure 2).6 patients in MASPORE had thrombotic events (3 with cerebral venous thrombosis and 3 with deep vein thrombosis (DVT)) while only 1 patient had DVT in HyperCVAD group. 11 patients in MASPORE group had at least 1 episode of grade 3 or more transaminitis, compared to 3 patients in HyperCVAD. 7 patients in HyperCVAD group had at least one episode of bacteremia during the course of treatment compared to 4 patients in the MASPORE group. Two treatment-related death were observed, both from HyperCVAD group.ConclusionsMASPORE protocol was well tolerated albeit higher rate of thrombotic events and transaminitis which most likely related to L-asparaginase, but with lower incidence of bacteremia and treatment related death. It showed a superior overall survival compared to HyperCVAD protocol and a trend towards improved leukemia free survival. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Pneumocystis Jiroveci Pneunomia Prophylaxis during Maintenance Therapy with Hyper-CVAD Regimens for Adult Acute Lymphoblastic Leukemia

BACKGROUNDPneumocystis jiroveci pneumonia (PCP) can be a deadly opportunistic infection in immunocompromised patients. Patients with acute lymphoblastic leukemia (ALL) are at risk for PCP due to their underlying disease, use of high doses of corticosteroids and receipt of lymphocyte-depleting chemotherapy. It is recommended that patients receive PCP prophylaxis during treatment for ALL. Trimethoprim/sulfamethoxazole (TMP/SMZ) is a common agent utilized but some practitioners are concerned about myelosuppression induced by TMP/SMZ. HyperCVAD regimens are the standard treatment strategy for ALL patients at our institution. Historically, PCP prophylaxis with TMP/SMZ was delayed until the beginning of maintenance therapy. This retrospective analysis evaluated PCP prophylaxis and incidence in ALL patients receiving maintenance therapy on a HyperCVAD regimen. Any influence of PCP prophylaxis on clinical outcomes was also evaluated. METHODSNewly diagnosed adult (≥ 18 yo) patients with ALL or lymphoblastic lymphoma who received at least one cycle of maintenance therapy on a HyperCVAD regimen between April 2000 to December 2016 were reviewed. Interim chart reviews were performed to identify the use of PCP prophylaxis and definite or suspected cases of PCP, as well as to document maintenance therapy doses or change in patient status, until the completion of maintenance therapy. Suspected PCP cases (missing microbiological documentation of Pneumocystis) were defined as those patients receiving PCP active therapy based on clinical presentation and imaging. RESULTSDuring the study period, 363 frontline ALL patients received at least one cycle of HyperCVAD maintenance therapy. 346 (198 males and 148 females) patients had sufficient documentation. Of these 346 patients, 145 never received PCP prophylaxis, 67 received i ntermittent PCP prophylaxis, and 134 received uninterrupted PCP prophylaxis throughout maintenance therapy. Only 3 cases of PCP (0.9%) were identified, one confirmed and 2 suspected. All cases occurred within the first 6 months of maintenance therapy and in patients never receiving PCP prophylaxis. The majority of patients receiving prophylaxis were on TMP/SMZ (97%); the most common regimen was 160 mg of the TMP component (1 DS tablet) twice daily two days per week. PCP prophylaxis rates have decreased over time - 55% of patients received uninterrupted PCP prophylaxis if initiated ALL maintenance therapy in 2000-2005 versus 10% of patients received uninterrupted maintenance if initiated ALL maintenance therapy in 2010-2016 (p=<0.001). Philadelphia-positive patients (106/346, 31%) received TKI-based maintenance therapy (TKI, corticosteroid, vincristine). Philadelphia-positive patients were less likely to receive uninterrupted PCP prophylaxis (p<0.0001). Doses of TKI were not statistically different between PCP prophylaxis groups. Philadelphia-negative patients received maintenance therapy containing mercaptopurine and methotrexate (plus corticosteroid, vincristine). Doses of mercaptopurine and methotrexate were not statistically different between PCP prophylaxis groups (p=0.75, p=0.4 respectively). ANC values were analyzed over time and were not significantly different between PCP prophylaxis groups (p=0.36 for never versus uninterrupted PCP prophylaxis). ALC values were also evaluated and were significantly lower in the uninterrupted PCP prophylaxis group at baseline, maintenance year 1 and maintenance year 2 (p=0.0464, p=0.0002, p=0.0001 respectively). Relapse rate, PFS and OS did not differ between the never, intermittent and uninterrupted PCP prophylaxis groups. CONCLUSIONSThe rate of PCP was low in this group of adult patients with newly diagnosed ALL undergoing maintenance therapy as part of a HyperCVAD regimen. All PCP cases occurred in patients not receiving PCP prophylaxis. TMP/SMZ prophylaxis had no significant effect on doses of ALL maintenance therapy provided as well as PFS and OS. TMP/SMZ remains a safe, effective choice for PCP prophylaxis in adult ALL patients. Given the low incidence of PCP in this population, future studies are warranted to identify risk factors that allow selection of patients who would benefit the most from PCP prophylaxis. DisclosuresJabbour:Bristol-Myers Squibb: Consultancy.

Outcomes in Acute Lymphoblastic Leukemia at the University of Wisconsin: An Institutional Review

Background: Adult acute lymphoblastic leukemia (ALL) treatment has undergone a significant shift in initial management over the previous decade. While pediatric patients have historically responded well to chemotherapy with cure rates around 90%, adult ALL patients have significantly worse outcomes with long-term cure rates in the mid 40% range. Several studies in the last decade have shown improved overall survival (OS) rates in adolescents and young adults (AYA) being treated with pediatric-type regimens. In 2011, our institution adopted guidelines recommending that all patients under the age of 40 at time of diagnosis undergo treatment with Berlin-Frankfurt-Münster (BFM) based regimen typically containing asparaginase. Patients over the age of 40 typically receive hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) based therapy with option to proceed either to maintenance chemotherapy vs transplantation following complete remission (CR). Prior to 2011, our group's approach to ALL patients was clinician-dependent, with some using BFM-based regimens and some using hyper-CVAD but without a standardized group approach.Methods: We conducted a single center retrospective review of patients with new diagnosis of acute lymphoblastic leukemia treated at the University of Wisconsin Hospital and Clinics between 2008-2016. Data collected included age at diagnosis (<40 vs >/= 40), WBC at presentation, B vs T cell subtype, Hyper-CVAD vs BFM based regimen, BCR/ABL status, transplant status, enrollment in clinical trial, overall survival (OS), relapse free survival (RFS), minimal residual disease status.Results: Overall there were 40 patients identified with new diagnosis of acute lymphoblastic leukemia. Estimated median OS for all new diagnoses was 3.93 years. There were a total of 23 patients over the age of 40 and 18 patients under the age of 40 at the time of diagnosis. There was no significant difference between the subgroup of under 40 vs over 40 in estimated median OS (p=0.103). There were 18 patients initiated on therapy with a hyper-CVAD based regimen vs 23 treated with non Hyper-CVAD regimen. Estimated median overall survival of patients treated with hyper-CVAD based regimen was 3.93 years vs 4.17 years for those treated with non Hyper-CVAD based regimen which was not significantly different (p=0.89). There were 10 patients who underwent allogeneic transplant in first remission. There was no significant difference in OS for those undergoing transplant vs not (p=0.42). There were 9 patients enrolled in clinical trial at time of diagnosis, all but one of whom were under the age of 30 and treated on Children's Oncology Group (COG) studies. Patients who enrolled in a clinical trial had a significantly higher estimated median overall survival 8.48 years vs 2.88 years (p=0.02). Minimal residual disease (MRD) status was evaluated after induction in 27 patients. Patients who achieved a negative MRD status had a significantly increased median OS vs those who had positive MRD testing (median not reached vs 2.15 years, p=0.001). Presenting WBC, B- vs T-cell disease, and BCR/ABL status were not significant predictors of OS.Conclusion: In 2011, the leukemia group at the University of Wisconsin adopted general guidelines for choosing initial treatment regimens for patients under vs over 40 years of age (BFM-based vs hyper-CVAD). Our single institution analysis showed that achieving MRD negative status was associated with improved estimated overall survival. This observation is consistent with published data that achieving MRD negative status is the single greatest prognostic indicator after the initiation of therapy. In addition, enrollment on a clinical trial was also associated with improved outcomes, though the number of patients on trial was significantly higher in the under-40 patient population. There was no significant difference in OS or RFS with treatment of Hyper-CVAD vs non Hyper-CVAD based regimen. Limitations of this study include a relatively small sample size and short follow up duration. These data indicate that achieving disease control as measured by MRD analysis with whichever initial regimen an institution is most familiar with may be the greatest single predictor of successful treatment. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Outcomes with Augmented Hyper-CVAD (AHCVAD), a Pediatric Inspired HCVAD-Based Regimen, for Adults Younger Than 50 Years of Age with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL)

Background: Numerous randomized studies in adolescents and young adults (AYA) with ALL have demonstrated significantly improved survival when therapy is intensified compared to standard dose adult protocols. However, little agreement exists as to the upper age limit where the benefits of pediatric-inspired regimens outweigh toxicity concerns. Similar to pediatric regimens, AHCVAD uses intensified doses of vincristine, dexamethasone, and pegaspargase and shows activity in relapsed patients (pts) with ALL (Faderl S et al: Clin Lymphoma Myel Leuk 2011). Here we evaluate the efficacy and safety of AHCVAD in younger adult pts with newly diagnosed ALL.Methods: Eligible were pts between ages 18 to 49 years with newly diagnosed adult B- or T-cell ALL. Excluded were pts with BCR-ABL-positive disease and Burkitt's leukemia. The hyper-CVAD regimen is well established and has been described in the past (Kantarjian et al: Cancer 2004). The AHCVAD regimen uses the hyper-CVAD backbone with four modifications: pts receive an intensified dose-schedule of vincristine 1.4 mg/m2 IV on days 1, 8, 15, 22 during cycle 1 and on days 1, 8, and 15 during cycles 3, 5, and 7; Dexamethasone is administered at 80 mg PO or IV on days 1-4 and 15-18 during cycles 1 and 40 mg PO or IV cycle 3, 5, and 7, and Pegaspargase 2500 units/m2 (capped at 3750 units) IV is given on day 4, and later changed to day 18 of cycles 1 to 8. Pts with CD20-positive ALL also received Rituximab at 375 mg/m2 on days 1 and15 of cycles 1 to 4. In pts with T-ALL, two cycles of nelarabine were given following AHCVAD cycles 4 and 5, respectively, and repeated during maintenance cycles 12 and 24. CNS prophylaxis was standard as published for hyper-CVAD.Prophylactic Enoxaparin 40 mg subcutaneously daily unless platelets < 30,000 was given to all pts treated after December 2016. Minimal residual disease (MRD) was assessed from marrow or blood by multiparameter flow cytometry after cycle 1, and subsequent cycles until negative, and every 4 months until the completion of maintenance, then every 6 months.Results: Between March 2014 and May 2017, 27 consecutive pts were enrolled. Median age was 29 yrs (19 to 49); 9 pts were more than 30 years old. The diagnosis was B-ALL in 66% and T-ALL in 33%. CR was achieved in 81% (22/27), with 84% (21/25) of these becoming MRD negative. The median time to CR was 0.85 months (mo) with 19 pts (70%) achieving CR following cycle 1 and an additional 3 pts achieving a CR following cycle 2. Pts received a median of 4 cycles. Fifteen pts (55%) proceeded to allogeneic stem cell transplantation. The median EFS and OS were not met with a median follow up of 16.6 months. At 36 months the EFS was 73% and OS was 77%. (Figure 1). Age was not a factor for early mortality (only 1 death during first 4 cycles) or thrombotic toxicities. Median OS survival was not influenced by age (20.6 mo for pts <30 yrs and 13.7 mo for pts >30 at 36 mo, p=.316). There were no deaths during the first 30 days of treatment.There was one treatment related death from septic shock while in CR during cycle 4 of consolidation. Five pts (18%) were transitioned to standard Hyper-CVAD due to toxicities. Most common reported toxicities that prompted a reduction in treatment intensity were infectious complications (n=4) and thrombosis (n=1). One pt experienced Grade 2 pancreatitis during cycle 2 that resolved with conservative management. There were 14 thrombotic events reported while on treatment (53%). The most common event was DVT (n=10). Two pts experienced pulmonary embolism and 1 pt experienced a grade 4 CNS thrombosis. Three pts experienced hemorrhagic complications. Ten of the pts received thrombosis prophylaxis. There was no significant difference in the rate of thrombosis or hemorrhage for pts based on cycle number, age or the use of prophylactic anticoagulation. There was no significant difference in the rate of complications observed in those pts receiving pegaspargase on day 4 vs day 18, but analysis was limited by sample size.Conclusion: AHCVAD is an active regimen for adults < 50 yrs with newly diagnosed ALL with a high rate of CR, MRD negativity, and low relapse rate. However significant toxicities were observed including hemorrhage, thrombosis and infection and intensive monitoring of these patients is required. Further exploration of this regimen appears warranted. [Display omitted] DisclosuresMcCloskey:Takeda: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Stanislaus:Novartis: Consultancy, Honoraria. Koprivnikar:Alexion: Consultancy, Speakers Bureau. Goldberg:Jazz: Speakers Bureau; Pfizer: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Ariad: Speakers Bureau; COTA: Employment, Equity Ownership; Celgene: Speakers Bureau. Faderl:Celator/Jazz: Employment, Equity Ownership.

An International Multicenter Retrospective Comparison of Induction Chemoimmunotherapy Regimens on Outcomes in Patients with Transplant-Eligible Mantle Cell Lymphoma

IntroductionThe optimal induction and conditioning regimen for patients with transplant eligible mantle cell lymphoma (MCL) remains unknown. Common approaches include the Nordic MCL2 regimen (rituximab (R), cyclophosphamide, vincristine, doxorubicin, prednisone (R-maxi-CHOP)) alternating with high-dose cytarabine (Geisler, Blood 2006) and R-Hyper CVAD/R-MA (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high dose methotrexate/cytarabine) (Romaguera JCO 2005). The aim of this study was to compare the efficacy of different induction and conditioning regimens in transplant eligible MCL patients.MethodsWe performed a multi-center retrospective analysis of MCL patients treated with induction chemo-immunotherapy and deemed fit enough for autologous stem cell transplant (ASCT) between December 2001 and December 2015. Patients were excluded if they did not receive rituximab with induction chemotherapy. Transplant eligibility was determined by the treating physician and patients were included if fit enough to undergo ASCT regardless of whether it was subsequently performed. Patient characteristics, prognostic factors and outcomes following treatment were collected. We used appropriate descriptive statistics to compare baseline characteristics between treatment groups, and calculated progression free (PFS), overall survival (OS) and follow up from date of diagnosis to date of disease progression or death from any cause, or death from any cause, respectively. Patients alive at last observation were censored. We used univariate Cox regression to identify associations between prognostic factors and outcomes, and covariates with P-values <0.1 were included in a Cox multivariate regression.ResultsWe identified 228 patients and grouped them according to induction regimen received. Their baseline characteristics, treatment and outcomes are summarized in Table 1. Overall, the 5 groups were mostly balanced in terms of baseline characteristics. Patients who underwent Nordic-like and Hyper-CVAD regimens were younger than the other groups. After a median follow up of 4.2 years (range 0.4-15), among the entire cohort the 4-year PFS was 62% (95%CI 54-69%) and OS was 84% (95%CI 78-88%). By univariate analysis, c-MIPI (combined MCL International Prognostic Index biologic index, with MIPI if Ki67 was not available), B symptoms, stage and bone marrow involvement at diagnosis were significantly associated with PFS; c-MIPI, blastoid histology, and B symptoms for OS.Induction chemo-immunotherapy regimen was not associated with PFS (Fig A) or OS (Fig B) by multivariate analysis and only c-MIPI high-risk group (HR=1.8 [95%CI 0.9-3.7], P=0.09) showed an adverse trend for PFS and similarly for OS (HR=2.7 [95%CI 1.1-6.4], P=0.02). Cytarabine-containing induction regimens were not significantly associated with PFS (HR=0.9 [95%CI 0.5-1.6], P=0.72) or OS (HR=1.5 [95%CI 0.7-3.0], P=0.27) by multivariate analysis. Considering only patients who received an ASCT, induction therapy was still not associated with PFS (P=0.81) or OS (P=0.51).Among patients who responded to induction and did not experience disease progression within 6 months of diagnosis, delivery of ASCT was associated with favorable PFS (P=0.01) (Fig C) and OS (P=0.07) by univariate analysis. PFS (HR=1.3 [95%CI 0.8-2.0], P=0.19) (Fig D) or OS (HR=0.9 [95%CI 0.5-1.6], P=0.75) were not affected by conditioning regimen among the same cohort. Use of the BEAM (carmustine, etoposide, cytarabine, melphalan) conditioning regimen was associated with inferior PFS relative to BuMel (busulfan and melphalan) (HR=2.0 [95%CI 1.1-3.6], P=0.02) but not OS (HR=1.1 [95%CI 0.5-2.3] P=0.77). Maintenance rituximab among transplanted patients was associated with neither PFS (P=0.94) nor OS (P=0.46) but numbers treated were low.ConclusionWithin the limits of a retrospective study and modest power for some comparisons, induction therapy did not influence ORR, PFS or OS. BuMel conditioning may result in superior disease control. Large prospective studies are required to define the optimal chemo-immunotherapy induction and conditioning regimen for MCL patients. [Display omitted] DisclosuresBishton:Roche: Other: Travel Sponsorship. Ritchie:Amgen Inc.: Honoraria. Schwarer:Novartis: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Roche: Honoraria; Amgen: Honoraria; Specialised Therapeutics: Honoraria. Tam:Janssen Cilag: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Opat:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Beigene: Research Funding; Mundipharma: Consultancy; Amgen: Research Funding. Hawkes:Roche: Other: Travel expenses; Bristol-Myers Squibb: Research Funding; Roche: Other: Travel expenses, Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Other: Travel expenses; Merck Serono: Research Funding; Merck Sharpe Dohme: Research Funding.

Clinical outcomes of patients with acute lymphoblastic leukemia receiving the hyper-CVAD regimen and assessment of the risk of hepatitis flares due to hepatitis B virus reactivation after chemotherapy.

IntroductionHyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone) has become a popular regimen for adults with acute lymphoblastic leukemia (ALL). We assessed the efficacy and tolerability of hyper-CVAD in the treatment of adult ALL.Material and methodsWe retrospectively reviewed ALL patients aged 18 or above receiving the hyper-CVAD regimen. We assessed complete remission rate and overall survival, as well as hepatitis B carrier rate and hepatitis flare due to hepatitis B virus (HBV) reactivation.ResultsFifty-two patients were treated with the hyper-CVAD regimen. The median age at diagnosis was 42 years; 27% of patients were Philadelphia (Ph) chromosome positive. The complete remission (CR) rate was 90.4% after the first cycle of chemotherapy. The induction mortality rate was 1.9%. Three patients required two cycles of hyper-CVAD to achieve CR. The median overall survival was 39.6 months and the 5-year overall survival was 50%. Age over 30 years and white blood cell count of more than 30 × 109/l were found to be prognostic for poor overall survival in multivariate analysis. The hepatitis B carrier rate was 17% in our cohort, and the rate of hepatitis flare due to HBV reactivation was 11% in patients with current infection.ConclusionsHyper-CVAD is feasible and tolerable with a good CR rate in the treatment of adult ALL patients. It is an option for the treatment of ALL. Antiviral prophylaxis should be considered in ALL patients with HBV infection to reduce the risk of HBV reactivation.

Ultrasensitive Next-Generation Sequencing-Based Measurable Residual Disease Assessment in Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia after Frontline Therapy: Correlation with Flow Cytometry and Impact on Clinical Outcomes

Ultrasensitive Next-Generation Sequencing-Based Measurable Residual Disease Assessment in Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia after Frontline Therapy: Correlation with Flow Cytometry and Impact on Clinical Outcomes

Prognostic Significance of Genetic Alterations in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Treated with Hyper-CVAD Plus Dasatinib or Hyper-CVAD Plus Ponatinib

Prognostic Significance of Genetic Alterations in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Treated with Hyper-CVAD Plus Dasatinib or Hyper-CVAD Plus Ponatinib

Frontline HCVAD with Nelarabine and Peg-Asparaginase in T-Acute Lymphoblastic Leukemia (T-ALL) and T-Lymphoblastic Lymphoma (T-LBL): Updated Results of a Phase II Trial

Frontline HCVAD with Nelarabine and Peg-Asparaginase in T-Acute Lymphoblastic Leukemia (T-ALL) and T-Lymphoblastic Lymphoma (T-LBL): Updated Results of a Phase II Trial

Survival outcomes in blastic plasmacytoid dendritic cell neoplasm by first-line treatment and stem cell transplant

AbstractBlastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with dismal clinical outcomes. Conventional chemotherapies such cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high-dose cytarabine and methotrexate (CVAD) have been commonly used for the BPDCN treatment until a recent study showed promising outcomes in patients treated with SL-401 (Tagraxofusp). In this single-institution retrospective study, we identified a total of 49 consecutive BPDCN patients. Among 42 patients who received treatment, hyper-CVAD regimen was associated with higher complete response rate compared with CHOP-based regimens or SL-401 (91% vs 50% vs 50%), although the difference did not achieve statistical significance. Furthermore, there was no significant overall survival (OS) difference between patients treated with SL-401 vs other chemotherapies as their first-line treatment (hazard ratio = 1.597; 95% CI, 0.460-5.548; P = .431). Of note, patients who received allogeneic stem cell transplant (allo-SCT) had significantly longer OS (hazard ratio = 0.160; 95% CI, 0.0453-0.56; P = .041). Extent of disease (skin vs bone marrow vs both) or younger age (<60 years old) did not have significant prognostic impact on OS. Collectively, our study confirmed the survival benefit of allo-SCT and suggests that conventional and intensive chemotherapies such as CHOP and hyper-CVAD as well as SL-401 would be comparable first-line choice for the BPDCN patients.

Hyper-CVAD regimen in combination with ofatumumab as frontline therapy for adults with Philadelphia chromosome-negative B-cell acute lymphoblastic leukaemia: a single-arm, phase 2 trial

The addition of rituximab to intensive chemotherapy improves outcomes in patients with B-cell acute lymphoblastic leukaemia. Ofatumumab is an anti-CD20 monoclonal antibody that binds to the small extracellular loop of CD20 and has greater in vitro complement-mediated cytotoxicity than rituximab. In this study, we assessed the activity and safety of ofatumumab in combination with chemotherapy in patients with Philadelphia chromosome (Ph)-negative CD20-positive B-cell acute lymphoblastic leukaemia. This was a single-arm, phase 2 trial done at the MD Anderson Cancer Center (Houston, TX, USA). Patients with newly diagnosed, Ph-negative B-cell acute lymphoblastic leukaemia or lymphoblastic lymphoma with CD20 expression of at least 1% were eligible. Patients were treated with up to eight courses of the hyper-CVAD regimen (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) on courses 1, 3, 5, and 7 alternating with high-dose methotrexate and cytarabine on courses 2, 4, 6, and 8. Ofatumumab was administered on days 1 and 11 of courses 1 and 3 and on days 1 and 8 of courses 2 and 4 for a total of eight doses. The first dose of ofatumumab was 300 mg intravenously and all subsequent doses were 2000 mg intravenously. Patients received 30 courses of maintenance therapy with 6-mercaptopurine, vincristine, methotrexate, and prednisone (POMP), with four intensification courses (high-dose methotrexate plus L-asparaginase and hyper-CVAD plus ofatumumab on courses 6-7 and 18-19). The primary endpoints were event-free survival, overall response, and overall survival. All enrolled patients were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, NCT01363128. Between Aug 26, 2011, and May 18, 2017, 69 patients (67 patients had B-cell acute lymphoblastic leukaemia and two had B-cell lymphoblastic lymphoma; median age 41 years [IQR 32-50]) were enrolled and treated, including 33 (48%) aged between 18 and 39 years. Nine (27%) of 33 patients had Ph-like acute lymphoblastic leukaemia. With a median follow-up of 44 months (26-53), 4-year event-free survival was 59% (95% CI 48-73); 69% (54-87) in adolescents and young adults aged 18-39 years. 4-year overall survival was 68% (58-81); 74% (60-91) in adolescents and young adults. The overall response rate was 98% (64 of 65 patients). The most common non-haematological grade 3 or 4 adverse events were infections (35 [54%] of 65 patients during induction and 53 [78%] of 68 patients during consolidation). Ten (14%) of 69 patients died in complete remission from sepsis (two [3%]), cardiac arrest (one [1%]), therapy-related acute myeloid leukaemia (two [3%]), and haematopoietic stem-cell transplantation complications (five [7%]). None of these deaths were considered related to ofatumumab treatment by the study investigators. The combination of hyper-CVAD plus ofatumumab is safe and active in adults with Ph-negative CD20-positive B-cell acute lymphoblastic leukaemia. Modifications of this regimen with the addition of novel monoclonal and bispecific antibody constructs targeting CD19 and CD22 might further improve outcomes and allow reduction in the intensity and duration of chemotherapy. Novartis.

Effect of Modified LMB 89± Rituximab Regimen on Long-Term Benefits for Patients's with Burkitt Lymphoma

To investigate the effect of modified LMB 89± rituximab regimen on long-term clinical benefit for patients with Burkitt lymphoma. Clinical data of 43 patients with Burkitt lymphoma were collected and retrospectively analyzed in the period from July 2006 to October 2017. Forty-three patients were divided into 2 groups, including Hyper-CVAD regimen, R-EPOCD regimen or VDCLP regimen treated group as control (20 patients) and modified regimen group with modified LMB 89±rituximab regimen (23 patients); the event-free survival (EFS) rate, overall survival (OS) rate, cumulative incidence of relapse (CIR), non-relapse mortality rate (NRM) and adverse reaction incidence of 2 groups were compared. At the same time, the efficacy analysis for patients of modified regimen group was performed according to age and using rituximab or no. The EFS rate and OS rate of modified regimen group were significantly higher than those of control group (P＜0.05). The CRR rate and NRM rate of modified regimen group were significantly lower than those of control group (P＜0.05). The EFS rate and OS rate of patients for ＜40 years old were significantly higher than those of patients for ≥40 years old in modified regimen group (P＜0.05). The EFS rate and OS rate of patients with rituximab were significantly higher than those of patients without rituximab in modified regimen group (P＜0.05). There was no significant difference in the adverse reaction incidence between 2 groups (P＞0.05). Modified LMB 89± rituximab regimen in the treatment of patients with Burkitt lymphoma can efficiently prolong survival time and shows the better safety; and the remigen combined with rituximab is more helpful to improve the clinical prognosis and show the better clinical effects for the patients≤40 years old.

FREQUENCY OF REMISSION AFTER TREATMENT WITH HYPER CVAD PROTOCOL IN NEWLY DIAGNOSED PATIENTS OF ACUTE LYMPHOBLASTIC LEUKEMIA PRESENTING TO JINNAH HOSPITAL LAHORE

ABSTRACT:&#x0D; OBJECTIVE: The objective of this study was to determine the frequency of complete and partial remission after 2 courses of hyper CVAD regimen in newly diagnosed patients of acute lymphoblastic leukemia (ALL).MATERIAL AND METHODS: This study was conducted on 100 patients of ALL presenting to the oncology department of Jinnah Hospital, Lahore and fulfilling the inclusion criteria from 01-012016 to 30-12-2016. Patients were undergone treatment with hyper CVAD regimen according to the standard protocol. Complete or partial remission rate was checked after 2 session of hyper CVAD regimen. CT scan (chest and abdomen) was performed for confirmation of extramedullary disease.&#x0D; RESULTS: The mean age of study population was 35.68 ± 8.69 years. There were 48% male patients while female patients were 52%. Complete remission was present in 72% patients. Partial remission was present in 24% patients. There was no significant association between complete remission and age (p-value=0.497). No significant association was found between partial remission and age (p-value=0.103). Significant association was found between partial remission and complete remission with gender having p-value=0.001 and 0.01 respectively.&#x0D; CONCLUSION: The frequency of complete and partial remission after 2 courses of hyper CVAD regimen in newly diagnosed patients of ALL was 72% and 24% respectively. Effect modifiers have no significant influence except gender.

Optimizing the use of the hyperCVAD regimen: Clinical vignettes and practical management.

Optimal administration of the hyperCVAD regimen requires awareness of its appropriate administration and supportive care practices. Practical management of anticipated toxicities and treatment of special patient populations with this regimen is reviewed.

Comparison between Hypercvad and CALLG2008 Protocol in Adult Patients with Newly Diagnosed Acute Lymphoblastic Leukemia:a Single Center Study

BACKGROUD: HyperCVAD is one of the most frequent used protocols in adult ALL in routine practice. On the other hand, the CALLG2008 protocol was a published protocol designed by the Chinese Acute Lymphoblastic Leukemia Cooperative Group for adult ALL. In this retrospective study, we analyzed 70 Chinese patients with adult ALL to compare the efficacy, safety and costs of HyperCVAD regimen in comparison to CALLG2008. METHODS: Pts ≥ 15 years old with previously untreated newly-diagnosed ALL were eligible. All pts provided IRB-approved informed consent before chemotherapy. HyperCVAD and CALLG2008 were given as initially described. Imatinib (400 mg daily) was administered concurrently in patients with Ph-positive ALL. Prophylactic antibiotics, antifungals, and antiviral agents were provided according to the institutional guidelines. Red blood cells and platelet transfusions were given for hemoglobin&lt;60 g/L and platelets≤10×109/L or if with hemorrhage. Granulocyte colony-stimulating factor was given routinely. Bone marrow aspiration was performed after the completion of the first course of induction chemotherapy to assess their response to treatment. All patients were evaluated for minimal residual disease (MRD) in bone marrow at the end of the first course of induction by 6-color multi-parametric flow cytometry analysis and reverse-transcription quantitative polymerase chain reaction (RT-qPCR). Primary endpoint of the study was CR rate after the first course of induction therapy. Complete remission (CR) was defined as having &lt;5% marrow blasts, a normalization of peripheral counts (neutrophil count ≥1 × 109/L, platelet count ≥100 × 109/L, and no abnormal peripheral blasts), and absence of extramedullary disease. The criteria for the positive and negative MRD are based on the experience of the European ALL MRD Detection Research Collaborative Group. Adverse events occurring during the first 8 weeks after the first course of induction therapy are reported. Other treatment outcomes including blood transfusion requirement, recovery day of neutrophil count were collected, as well as detailed data regarding hospitalization time, complications and costs. RESULTS: Thirty patients were treated with HyperCVAD, and 40 with CALLG2008. Pre-treatment characteristics are shown in the Table 1. After the first course of induction chemotherapy, complete remission was obtained in 83% and 78% of patients, respectively. The CR rate did not vary significantly by different regimens, gender, age, immunophenotype. However, 96% of those with cytogenetic or molecular evidence of the Philadelphia (Ph) chromosome and 76% of those without such evidence achieved a CR (P=0.045). In Ph-negative group, MRD-negative rates were found to be significantly higher with HyperCVAD (58% vs 27%, P=0.036). The median durations of neutrophil recovery of CALLG2008 group was 4 days longer than HyperCVAD group (P=0.038). Moreover, grade 3-4 thrombocytopenic (&lt;500/μl) was more frequent on CALLG2008 regimens compared with the HyperCVAD regimens (90% vs 63%; P=0.007). Accordingly, a lower platelet transfusion rate was observed in favor of the HyperCVAD group (47% vs 73%, P=0.007). The CALLG2008 regimen had more all-grade hepatic toxicity than HyperCVAD regimen (53% vs 27%; P=0.03). Grade 3-4 hypofibrinogenemia was more frequent on CALLG2008 regimen compared with hyper-CVAD regimen (33% vs 7%; P=0.009). The average time to stay of the first course of chemotherapy were 19.4±3.5 and 24.2±8.6 days in HyperCVAD and CALLG2008 groups, respectively (P=0.002). The average drug-related costs for patients treated with HyperCVAD were significantly lower compared with that for those treated with CALLG2008 (30981.7 vs 59422.9 yuan, P=0.010). CONCLUSION: Although HyperCVAD and CALLG2008 regimens showed relatively similar early CR rate, the former yields deep remissions more powerfully in Ph-negative ALL. Additionally, HyperCVAD was more favorable in hematopoietic recovery than CALLG2008. Differences were also observed in terms of less complications, shorter hospitalization and lower drug-related expenditure in favor of HyperCVAD group. Disclosures No relevant conflicts of interest to declare.

Phase II Study of the Hyper-CVAD Regimen in Combination with Ofatumumab (HCVAD-O) As Frontline Therapy for Adult Patients (pts) with CD20-Positive B-Cell Acute Lymphoblastic Leukemia (B-ALL)

Phase II Study of the Hyper-CVAD Regimen in Combination with Ofatumumab (HCVAD-O) As Frontline Therapy for Adult Patients (pts) with CD20-Positive B-Cell Acute Lymphoblastic Leukemia (B-ALL)