Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome–positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study

Blood ◽  
2007 ◽  
Vol 110 (7) ◽  
pp. 2309-2315 ◽  
Author(s):  
Oliver Ottmann ◽  
Hervé Dombret ◽  
Giovanni Martinelli ◽  
Bengt Simonsson ◽  
Francois Guilhot ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Study Drug ◽  
Cytogenetic Response ◽  
Phase 2 ◽  
Effective Treatment Option ◽  
Imatinib Resistance ◽  
Phase 2 Study

Patients with Philadelphia (Ph) chromosome–positive acute lymphoblastic leukemia (ALL) have a rapid disease course and a poor prognosis. Dasatinib, a novel, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases, has previously induced responses in patients with imatinib-resistant or -intolerant Ph-positive ALL. We present the interim results of a phase 2 study designed to further assess the efficacy, safety, and tolerability of dasatinib 140 mg in this patient population (n = 36). With a minimum follow-up of 8 months, treatment with dasatinib resulted in substantial hematologic and cytogenetic response rates. Major hematologic responses were achieved in 42% (15/36) of patients, 67% of whom remained progression-free. Complete cytogenetic responses were attained by 58% (21/36) of patients. The presence of BCR-ABL mutations conferring imatinib resistance did not preclude a response to dasatinib. Dasatinib was also tolerable, with 6% (2/36) of patients discontinuing therapy as a result of study-drug toxicity. Most adverse events (AEs) were grade 1 or 2; febrile neutropenia was the most frequent severe AE, but this and other cytopenias were manageable with dose reduction. Dasatinib represents a safe and effective treatment option and an important therapeutic advance for patients with Ph-positive ALL. This trial was registered at www.clinicaltrials.gov as #CA180015.

scholarly journals Phase 2 study of pembrolizumab for measurable residual disease in adults with acute lymphoblastic leukemia

2020 ◽  
Vol 4 (14) ◽  
pp. 3239-3245
Author(s):  
Ryan D. Cassaday ◽  
Kelsey-Leigh A. Garcia ◽  
Jonathan R. Fromm ◽  
Mary-Elizabeth M. Percival ◽  
Cameron J. Turtle ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Philadelphia Chromosome ◽  
Stevens Johnson Syndrome ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Measurable Residual Disease

Abstract The presence of measurable residual disease (MRD) in acute lymphoblastic leukemia (ALL) confers a poor prognosis. CD19-targeted immunotherapy is effective against MRD but is logistically challenging, potentially toxic, and not applicable to T-cell ALL. We thus hypothesized that inhibition of PD-1 with pembrolizumab could also be effective for MRD, but without lineage restriction. The primary objective of this phase 2 study was to evaluate the efficacy of pembrolizumab in patients with ALL and MRD. Key eligibility criteria included adults with B- or T-cell ALL and MRD detectable by multiparameter flow cytometry or quantitative polymerase chain reaction from bone marrow aspirate (BMA) despite chemotherapy (plus ABL kinase inhibitor if Philadelphia chromosome positive). Pembrolizumab 200 mg IV was given every 3 weeks. Response was assessed by BMA using methods that previously detected MRD. The primary end point was complete MRD response rate. We stopped enrollment early; only 1 of 12 (8%) experienced a complete MRD response, which lasted 3 weeks. Interestingly, this patient had previously received hematopoietic cell transplantation and CD19-targeted chimeric antigen receptor–modified T-cell therapy and was the only patient to experience an immune-related adverse event from pembrolizumab (grade 3 Stevens-Johnson syndrome). Median overall survival from enrollment was 12.7 months. In summary, pembrolizumab had minimal activity against MRD but was generally well tolerated. These data can be compared with ongoing anti-PD-1 combination studies in ALL, and they further establish the role of trials specifically for patients with MRD. This trial was registered at www.clinicaltrials.gov as #NCT02767934.

scholarly journals A Phase 2 Study of Ruxolitinib with Chemotherapy in Children with Philadelphia Chromosome-like Acute Lymphoblastic Leukemia (INCB18424-269/AALL1521): Dose-Finding Results from the Part 1 Safety Phase

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 555-555 ◽  
Author(s):  
Sarah K. Tasian ◽  
Albert Assad ◽  
Deborah S Hunter ◽  
Yining Du ◽  
Mignon L. Loh
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Induction Chemotherapy ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Phase 2 Study ◽  
Multi Agent

Abstract Background: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype occurring in 15-30% of older children and adolescents/young adults (AYAs) with B-ALL. Ph-like ALL is associated with high relapse rates and poor survival despite intensive multi-agent cytotoxic chemotherapy. Development of successful treatment strategies to decrease relapse and improve cure rates in patients with Ph-like ALL remains a major therapeutic gap. Rearrangements of cytokine receptor-like factor 2 (CRLF2-R) with frequent concomitant JAK2 point mutations occur in 50% of Ph-like ALL cases and induce constitutive JAK/STAT and other kinase signaling. An additional 15-20% of Ph-like ALL harbors other JAK pathway alterations, such as JAK2 or EPOR rearrangements, that similarly activate JAK/STAT signaling. Ruxolitinib is a potent, selective JAK1/JAK2 inhibitor with demonstrated activity in preclinical Ph-like ALL models and clinical safety as monotherapy in children with relapsed/refractory cancers. We report the initial safety of ruxolitinib in combination with post-induction chemotherapy in children and AYAs with newly-diagnosed high-risk (HR) Ph-like ALL with CRLF2-R or other JAK pathway alterations treated on the non-randomized, 2-part phase 2 study INCB18424-269 (AALL1521; NCT02723994). Methods: Patients aged 1-21 years at time of diagnosis with HR B-ALL and eligible Ph-like genetic lesions who had completed 4-drug induction chemotherapy as per the Children's Oncology Group (COG) AALL1131 study (NCT02883049) were eligible to participate. Patients were stratified into 4 cohorts by genetic alterations and end-induction flow cytometric minimal residual disease (MRD) status: cohort A = CRLF2-R JAK-mutant, MRD+; B = CRLF2-R JAK-wild-type, MRD+; C = other JAK pathway alterations, MRD+, D = any CRLF2-R or JAK pathway alteration, MRD-. Patients commenced treatment on the INCB18424-269/AALL1521 study at consolidation with ruxolitinib orally twice daily in combination with augmented Berlin-Frankfurt-Münster (aBFM) post-induction chemotherapy as per AALL1131. Five discontinuous dose levels (10-50 mg/m2/dose 14-days-on/14-days-off per cycle [DL-2 to DL2]) and one continuous DL1b (40 mg/m2/dose × 28 days per cycle) of ruxolitinib with aBFM chemotherapy were explored via a standard rolling 6 design. Dose-limiting toxicities (DLTs) were assessed through Day 29 of delayed intensification (DI) and defined as hematologic and non-hematologic toxicity with higher grade or more prolonged duration than observed in children with treated with identical chemotherapy (without ruxolitinib) on other COG HR B-ALL trials. Pharmacokinetic (PK) and pharmacodynamic (PD) analyses were conducted using serial blood samples obtained from patients during consolidation therapy. Results: Forty patients (pts) were enrolled in Part 1 (cohort A, n=10; B, n=9; C, n=5; D, n=16). Four patients discontinued study treatment before the Day 29 DI timepoint, 3 of whom were replaced. Patients had a median age of 14 years, and 67.5% were male. Treatment-emergent adverse events occurred in all patients and included anemia (75%), platelet count decrease and/or thrombocytopenia (65%), febrile neutropenia (72.5%), and AST or ALT increase (57.5%). Thirty-three patients had Grade 3/4 events deemed possibly related to ruxolitinib without identified DLTs. Eleven patients in Part 1 (27.5%) discontinued study therapy for various reasons: CNS relapse (2 pts), end-consolidation MRD+ (4 pts), multi-system organ dysfunction (MSOD; 2 pts), elective MRD- stem cell transplantation (1 pt), psychosocial/compliance issues (2 pts). One patient died of septic shock and MSOD not attributed to ruxolitinib. Preliminary analysis of plasma drug levels at 4 hours post-dose was consistent with the known PK profile of ruxolitinib. PD studies demonstrated dose-dependent inhibition of target phosphoproteins and, importantly, sustained inhibition of phosphorylated STAT5 with continuous ruxolitinib dosing at DL1b. Discussion: These findings demonstrate safety and tolerability of ruxolitinib in combination with intensive multi-agent chemotherapy in children and AYAs with newly-diagnosed HR CRLF2-R/JAK pathway-mutant Ph-like ALL and support continued investigation of treatment efficacy in Part 2 of this trial. Disclosures Tasian: Aleta Biopharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Research Funding; Incyte Corporation: Research Funding. Assad:Incyte Corporation: Employment, Equity Ownership. Hunter:Incyte Corporation: Employment. Du:Incyte Corporation: Employment.

scholarly journals Marqibo®, Vincristine Sulfate Liposome Injection, for the Treatment of Advanced, Relapsed or Refractory Philadelphia Chromosome-Negative (Ph-) Acute Lymphoblastic Leukemia (ALL) in an Adolescent Young Adult (AYA) Population

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1291-1291 ◽  
Author(s):  
Gary J Schiller ◽  
Lloyd E. Damon ◽  
Wendy Stock ◽  
Steven E Coutre ◽  
Pamela Hsu ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Young Adult ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Adult Population ◽  
Philadelphia Chromosome ◽  
Phase 2 ◽  
Vincristine Sulfate ◽  
Phase 2 Study ◽  
The Us

Abstract Background: Patients aged 15 to 39 years old constitute the Adolescent Young Adult (AYA) population. In the US, leukemias represent ~6% of all cancers in this population with the incidence of Acute Lymphoblastic Leukemia (ALL) gradually decreasing with age as the incidence of acute and chronic myeloid leukemias (AML, CML, respectively) increase; ALL occurs at approximately twice the rate of AML in 15- to 19-year olds. Further studies are needed to define the unique features of leukemia in AYA patients, and to better assess and optimize treatment regimens. Marqibo®, vincristine sulfate liposome injection, uses a novel sphingomyelin and cholesterol nanoparticle that facilitates vincristine dose intensification without exacerbation of its toxicity, i.e., it has a wider therapeutic index than standard formulation vincristine. This formulation has also been shown to enhance the penetration and concentration of vincristine into tumors, and prolong plasma circulation time in non-clinical experiments. Marqibo is approved in the US for the treatment of adult patients with Philadelphia chromosome negative (Ph-) ALL in second or greater relapse, whose disease has progressed following two or more previous lines of therapy. We performed a retrospective analysis of data from the Phase 2 RALLY clinical trial (n=65) to examine the effects of Marqibo in the subgroup of the AYA population. The Phase 2 study results of the entire study demonstrated that treatment with single-agent Marqibo resulted in an Overall Response Rate (ORR) of 35%, with 20% of patients achieving a Complete Response (CR) or CR with Incomplete Blood Count Recovery (CRi) (O'Brien, S., 2012 J Clin Oncol). Methods: Data from the RALLY Phase 2 study of Marqibo were analyzed retrospectively to examine only the relapsed or refractory Ph- ALL patients 39 years of age and younger (n=44). In this study, Marqibo (2.25mg/m2) was administered via IV over 60 minutes without dose capping, once per week until response, progression, toxicity or hematopoietic transplant. Results: The median age of the 44 patients was 27 (range: 19-39), 57% were male, 82% had B-cell ALL and 18% had T-cell ALL. 84% had ECOG performance status of 0 or 1. The number of previous treatments ranged from 2-6. 41% had 2 prior lines of treatment, 41% had 3 prior lines of treatment, 16% had 4 prior lines of treatment and 2% had 6 prior lines of treatment. In addition, 59% of patients had previously received a hematopoietic cell transplant. The ORR in the AYA population was 39%, with 25% of patients achieving a CR or CRi. Overall, the safety profile of Marqibo was similar to that in the older adult population, with 35 (79.5%) patients having a treatment-related adverse event, of any grade, on study. The most common treatment-related adverse events, of any grade, in the AYA population were constipation (34%) and peripheral neuropathy (32%). Conclusions: Marqibo (vincristine sulfate liposome injection) was shown to have clinical benefit in AYA patients with relapsed or refractory Ph- ALL with similar safety and efficacy profiles compared to the entire adult population (range: 19-83). Disclosures Schiller: Sunesis: Honoraria, Research Funding. Damon:Atara: Consultancy; Sunesis: Research Funding; McGraw Hill: Other: Chapter Royalties; Sigms Tau: Research Funding. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees. Coutre:Pharmacyclics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Douer:Gilead: Consultancy.

scholarly journals Marrow Transplants From Unrelated Donors for Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Blood ◽  
1997 ◽  
Vol 90 (4) ◽  
pp. 1410-1414 ◽  
Author(s):  
Jorge Sierra ◽  
Jerry Radich ◽  
John A. Hansen ◽  
Paul J. Martin ◽  
Effie W. Petersdorf ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Early Stage ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Unrelated Donor ◽  
Effective Treatment Option ◽  
Patients At Risk ◽  
Unrelated Donors ◽  
First Relapse ◽  
Philadelphia Chromosome Positive

Transplantation of marrow from unrelated donors was investigated in patients with Philadelphia chromosome-positive (Ph1+) acute lymphoblastic leukemia (ALL) who lacked a suitable family donor. Eighteen patients underwent transplantation at our center between 1988 and 1995. The median patient age was 25 years (range, 1.7 to 51 years). Seven patients were in first complete remission, 1 in second remission, 3 in first relapse, and the remaining 7 had more advanced or chemotherapy refractory leukemia at transplant. All patients were conditioned with cyclophosphamide and total body irradiation followed by marrow transplants from closely HLA-matched, unrelated volunteers. Posttransplant graft-versus-host disease (GVHD) prophylaxis included methotrexate with either cyclosporine or FK506. Graft failure was not observed. Severe (grades III-IV) GVHD appeared in 6 of 17 evaluable patients and chronic extensive GVHD in 7 of 13 patients at risk. Five patients had recurrent ALL after transplantation and another 4 died from causes other than leukemia. Six patients transplanted in first remission, 2 in first relapse, and 1 in second remission remain alive and leukemia-free at a median follow-up of 17 months (range, 9 to 73 months). The probability of leukemia-free survival at 2 years is 49% ± 12%. These data indicate that unrelated donor marrow transplantation is an effective treatment option for patients with early stage Ph1+ ALL without a family match and suggest that in such patients an unrelated donor search should be initiated as soon as possible after diagnosis.

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