Daratumumab for relapsed/refractory Philadelphia-positive acute lymphoblastic leukemia.
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ABSTRACT:
SUBMITTER: Ganzel C
PROVIDER: S-EPMC6165821 | biostudies-literature | 2018 Oct
REPOSITORIES: biostudies-literature
Publications
Daratumumab for relapsed/refractory Philadelphia-positive acute lymphoblastic leukemia.
Ganzel Chezi C Kharit Mira M Duksin Chen C Rowe Jacob M JM
Haematologica 20180628 10
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Project description:To overcome the unfavorable outcome of refractory/relapsed (R/R) Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) and conduct allogeneic stem cell transplantation (allo-SCT) safely, we designed a sequential therapy involving a single cycle of Inotuzumab ozogamicin (InO) and Blinatumomab (Blina). Two heavily treated and aged patients with R/R Ph+ALL were treated with the therapy. Both of them achieved complete molecular remission without cytokine release syndrome and underwent allo-SCT without veno-occlusive disease/sinusoidal obstruction syndrome. Although appropriate central nervous system prophylaxis should be added, the InO-Blina sequential therapy is a promising strategy for treating R/R Ph+ALL as a bridging regimen before allo-SCT.
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Project description:Acute lymphoblastic leukemia (ALL) remains a disease with poor outcomes in adults. While induction chemotherapy achieves a complete remission in almost 90% of patients, the majority will relapse and die of their disease. Relapsed ALL is associated with a high reinduction mortality and chemotherapy resistance, with allogeneic hematopoietic stem cell transplantation offering the only therapy with curative potential. However, there is no efficacious and well tolerated standard regimen accepted as a "bridge" to allogeneic stem cell transplantation or as definitive treatment for patients who are not transplant candidates. Vincristine is an active drug in patients with ALL, but its dose intensity is limited by neurotoxicity, and its full potential as an anticancer drug is thus not realized. Encapsulation of vincristine into sphingomyelin and cholesterol nanoparticle liposomes facilitates dose-intensification and densification to enhanced target tissues with reduced potential for toxicity. Vincristine sulfate liposome injection (VSLI) is associated with significant responses in clinically advanced ALL, and has recently been approved by the US Food and Drug Administration for treatment of relapsed and clinically advanced Philadelphia chromosome-negative ALL. This review provides an overview of the preclinical and clinical studies leading to the approval of VSLI for the treatment of relapsed and refractory ALL, and suggests potential areas of future clinical development.
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| S-EPMC9278812 | biostudies-literature
Project description:Aim:Chinese adults with relapsed/refractory Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (Ph- ALL) have poor outcomes. Patients & methods:We conducted a nationwide, retrospective, observational study to assess outcomes in this patient population. Results:Of the 270 enrolled patients, 31% of patients at last salvage achieved complete remission (CR) or CR with partial hematologic recovery (CRh), with median time to CR/CRh of 30 days and median CR/CRh duration of 2.7 months. The CR/CRh rate was more favorable with earlier versus later lines of salvage (41, 24 and 17% at first, second and third or later salvages, respectively). Conclusion:This dataset serves as an important reference of real-world outcomes using currently available chemotherapy regimens for high-risk Chinese adults with relapsed/refractory Ph- ALL.
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Project description:The majority of adult patients affected by B-cell acute lymphoblastic leukemia (B-ALL) will relapse after an initial response, while approximately 20% will display primary resistant disease. Patients suffering from relapsed/refractory B-ALL have a very poor outcome. Allogeneic hematopoietic cell transplantation (HCT) still represents the only curative approach, but is not so frequently feasible, because of patient's fitness, donor availability, and the ability to achieve a remission prior to HCT. The estimated remission rates with conventional cytotoxic agents are around 30%, but they are short-lived. These disappointing results led to the introduction of new immunologic-based treatments-blinatumomab and inotuzumab. They produced a substantial improvement in terms of response rates, with the ability, in most cases, to induce a minimal residual disease (MRD)-negative status. Similarly, T cells engineered to express a CD19-specific chimeric antigen receptor (CAR-T) have yielded sensational results among patients with relapsed/refractory B-ALL, with unexpectedly high MRD-negative complete remissions rates. However, the first studies looking at long-term outcomes after CAR-T infusions told us that a significant fraction of such responses are not durable, and may benefit from a consolidation approach such as an allogeneic HCT.
| S-EPMC8432388 | biostudies-literature
Project description:Relapsed/refractory (R/R) Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL) and lymphoid blast phase of chronic myeloid leukemia (LBP-CML) have poor outcomes. We designed a phase 1/2 study combining inotuzumab ozogamicin with bosutinib for this patient population. Patients with T315I mutation were excluded. Bosutinib was administered daily at three dose levels (300 mg/d, 400 mg/d, 500 mg/d) in a 3 + 3 design. Inotuzumab ozogamicin was dosed weekly during cycle one, and once every 4 weeks subsequently for a total of six cycles. The primary objective was to determine the safety and the maximum tolerated dose (MTD) of bosutinib in combination with inotuzumab ozogamicin. Eighteen patients were enrolled (Ph-positive ALL, n = 16; LBP-CML, n = 2). The median age was 62 years (range, 19-74) and the median number of prior therapies was one (range, 1-5). Dose limiting toxicities included grade 3 skin rash and bosutinib 400 mg daily was determined as the MTD. The most frequent grade 3/4 treatment-emergent adverse events were thrombocytopenia (60%) and neutropenia (38%). A complete response (CR) / CR with incomplete count recovery (CRi) was achieved in 15/18 (83%) patients; 11/18 (61%) patients achieved negative measurable residual disease by flow cytometry. Complete molecular response was noted in 10/18 (56%) patients. The 30-day mortality was 0%. After a median follow-up of 44 months, the median duration of response and overall survival were 7.7 months and 13.5 months, respectively. Six patients had a subsequent allogeneic stem cell transplant. No patient developed veno-occlusive disease. Inotuzumab ozogamicin with bosutinib was well tolerated in R/R Ph-positive ALL and LBP-CML.
| S-EPMC9096877 | biostudies-literature
Project description:BACKGROUND:A single-arm, phase 2 trial demonstrated the efficacy and safety of blinatumomab, a bispecific T-cell-engaging antibody construct, in patients with relapsed/refractory (r/r) Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), a rare hematologic malignancy with limited treatment options. This study compared outcomes with blinatumomab with those of a historical control treated with the standard of care (SOC). METHODS:The blinatumomab trial enrolled adult patients with Ph+ ALL who were r/r to at least 1 second-generation tyrosine kinase inhibitor (n = 45). Propensity score analysis (PSA) was used to compare outcomes with blinatumomab with those of an external cohort of similar patients receiving SOC chemotherapy (n = 55). The PSA mitigated confounding variables between studies by adjusting for imbalances in the age at diagnosis and start of treatment, sex, duration from diagnosis to most recent treatment, prior allogeneic hematopoietic stem cell transplantation, prior salvage therapy, and number of salvage therapies. Bayesian data augmentation was applied to improve power to 80% with data from a phase 3 blinatumomab study in r/r Philadelphia chromosome-negative ALL. RESULTS:In the PSA, the rate of complete remission or complete remission with partial hematologic recovery was 36% for blinatumomab and 25% for SOC, and this resulted in an odds ratio of 1.54 (95% confidence interval [CI], 0.61-3.89) or 1.70 (95% credible interval [CrI], 0.94-2.94) with Bayesian data augmentation. Overall survival favored blinatumomab over SOC, with a hazard ratio of 0.81 (95% CI, 0.57-1.14) or 0.77 (95% CrI, 0.61-0.96) with Bayesian data augmentation. CONCLUSIONS:These results further support blinatumomab as a treatment option for patients with r/r Ph+ ALL.
| S-EPMC7003760 | biostudies-literature
Project description:The introduction of agents targeted at specific molecular events is changing the treatment paradigms in a number of malignancies. Historically, we have relied entirely on DNA-interactive, cytotoxic drugs for treating patients with leukemia. Increased understanding of the leukemic cell biology and pathogenesis, and the ways they evade the immune surveillance mechanisms, will likely lead to the development of more effective agents, and regimens less reliant on chemotherapy, able to achieve deep levels of disease eradication. In Philadelphia chromosome-positive acute lymphoblastic leukemia, the introduction of increasingly potent tyrosine kinas inhibitors (TKIs) has revolutionized therapy. These drugs have been established as the cornerstone of any therapeutic strategy in this disease, and a number of trials have better defined the best ways to incorporate them into the established paradigms. Despite using TKIs, we have continued to remain reliant on cytotoxic chemotherapy regimens and allogeneic hematopoietic cell transplant to achieve the best long-term outcomes. However, with the introduction of more potent TKIs and other novel agents, as well as better methods for monitoring minimal/measurable residual disease, we are entering an era where we hope to diminish our reliance on transplantation and cytotoxic chemotherapy in this disease.
| S-EPMC7042663 | biostudies-literature
Project description:PurposeRelapsed adult acute lymphoblastic leukemia (ALL) is associated with high reinduction mortality, chemotherapy resistance, and rapid progression leading to death. Vincristine sulfate liposome injection (VSLI), sphingomyelin and cholesterol nanoparticle vincristine (VCR), facilitates VCR dose-intensification and densification plus enhances target tissue delivery. We evaluated high-dose VSLI monotherapy in adults with Philadelphia chromosome (Ph) -negative ALL that was multiply relapsed, relapsed and refractory to reinduction, and/or relapsed after hematopoietic cell transplantation (HCT).Patients and methodsSixty-five adults with Ph-negative ALL in second or greater relapse or whose disease had progressed following two or more leukemia therapies were treated in this pivotal phase II, multinational trial. Intravenous VSLI 2.25 mg/m(2), without dose capping, was administered once per week until response, progression, toxicity, or pursuit of HCT. The primary end point was achievement of complete response (CR) or CR with incomplete hematologic recovery (CRi).ResultsThe CR/CRi rate was 20% and overall response rate was 35%. VSLI monotherapy was effective as third-, fourth-, and fifth-line therapy and in patients refractory to other single- and multiagent reinduction therapies. Median CR/CRi duration was 23 weeks (range, 5 to 66 weeks); 12 patients bridged to a post-VSLI HCT, and five patients were long-term survivors. VSLI was generally well tolerated and associated with a low 30-day mortality rate (12%).ConclusionHigh-dose VSLI monotherapy resulted in meaningful clinical outcomes including durable responses and bridging to HCT in advanced ALL settings. The toxicity profile of VSLI was predictable, manageable, and comparable to standard VCR despite the delivery of large, normally unachievable, individual and cumulative doses of VCR.
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Project description:The t(9;22)(q34;q11) or Philadelphia chromosome creates a BCR-ABL1 fusion gene encoding for a chimeric BCR-ABL1 protein. It is present in 3-4% of pediatric acute lymphoblastic leukemia (Ph(+) ALL), and about 25% of adult ALL cases. Prior to the advent of tyrosine kinase inhibitors (TKI), Ph(+) ALL was associated with a very poor prognosis despite the use of intensive chemotherapy and frequently hematopoietic stem-cell transplantation (HSCT) in first remission. The development of TKIs revolutionized the therapy of Ph(+) ALL. Addition of the first generation ABL1 class TKI imatinib to intensive chemotherapy dramatically increased the survival for children with Ph(+) ALL and established that many patients can be cured without HSCT. In parallel, the mechanistic understanding of Ph(+) ALL expanded exponentially through careful mapping of pathways downstream of BCR-ABL1, the discovery of mutations in master regulators of B-cell development such as IKZF1 (Ikaros), PAX5, and early B-cell factor (EBF), the recognition of the complex clonal architecture of Ph(+) ALL, and the delineation of genomic, epigenetic, and signaling abnormalities contributing to relapse and resistance. Still, many important basic and clinical questions remain unanswered. Current clinical trials are testing second generation TKIs in patients with newly diagnosed Ph(+) ALL. Neither the optimal duration of therapy nor the optimal chemotherapy backbone are currently defined. The role of HSCT in first remission and post-transplant TKI therapy also require further study. In addition, it will be crucial to continue to dig deeper into understanding Ph(+) ALL at a mechanistic level, and translate findings into complementary targeted approaches. Expanding targeted therapies hold great promise to decrease toxicity and improve survival in this high-risk disease, which provides a paradigm for how targeted therapies can be incorporated into treatment of other high-risk leukemias.
| S-EPMC3971203 | biostudies-literature