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BackgroundPatients with relapsed/refractory (R/R) Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) have a poor prognosis and limited treatment options.MethodsThe efficacy of inotuzumab ozogamicin (InO), a humanized anti-CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin, was evaluated in R/R ALL patients in the phase 1/2 study 1010 (NCT01363297) and open-label, randomized, phase 3 study 1022 (INO-VATE; NCT01564784). This analysis focused specifically on Ph+ R/R ALL patients. In study 1022, Ph+ patients were randomly assigned 1:1 to InO (n = 22) or standard intensive chemotherapy (SC) (n = 27) and 16 Ph+ patients in study 1010 received InO.ResultsIn study 1022, rates of complete remission/complete remission with incomplete hematologic recovery (CR/CRi) and minimal residual disease (MRD) negativity (patients achieving CR/CRi) were higher with InO (CR/CRi = 73%; MRD = 81%) versus SC (CR/CRi = 56%; MRD = 33%). The corresponding rates in study 1010 were 56% (CR/CRi) and 100% (MRD). The hematopoietic stem cell transplantation (HSCT) rate in study 1022 was 41% versus 19% for InO versus SC; however, there was no benefit in overall survival (median OS: 8.7 vs 8.4 months; hazard ratio, 1.17 [95% CI, 0.64-2.14]). The probability of being event-free (progression-free survival) at 12 months was greater with InO versus SC (20.1% vs 4.8%).ConclusionGiven the substantial improvement in responses and rates of HSCT, InO is an important treatment option for patients with R/R Ph+ ALL. Future studies need to consider better characterization of disease characteristics, more sensitive MRD measurements, MRD-directed therapy before HSCT, and potentially combination therapies, including tyrosine kinase inhibitors.

BackgroundInotuzumab ozogamicin (InO) is an antibody-drug conjugate used for adults with relapsed/refractory B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). The INotuzumab Ozogamicin trial to inVestigAte Tolerability and Efficacy (INO-VATE) previously reported improved outcomes with InO versus standard-of-care (SoC) chemotherapy. This article reports the final INO-VATE results (≥2 years of follow-up) and additional analyses of patient characteristics associated with improved outcomes.MethodsBetween August 27, 2012, and January 4, 2015, this multicenter, parallel, open-label, phase 3 trial randomized 326 adults with relapsed/refractory ALL to InO (n = 164) or SoC (n = 162); 307 received 1 or more doses of the study drug (164 in the InO arm and 143 in the SoC arm).ResultsThe complete remission (CR)/complete remission with incomplete hematologic recovery (CRi) rate was higher with InO versus SoC (73.8% vs 30.9%; 1-sided P

Inotuzumab ozogamicin (InO) is an antibody‐drug conjugate approved for the treatment of relapsed/refractory B‐cell acute lymphoblastic leukemia (ALL). Several clinical trials are investigating InO in combination with low‐intensity chemotherapy or other anti‐ALL–targeted therapies in the salvage and frontline settings, notably in older adults who often cannot tolerate intensive chemotherapy and tend to have higher‐risk disease. InO is also increasingly used to bridge patients to hematopoietic stem cell transplantation (HSCT), in sequence with chimeric antigen receptor T‐cell therapy, to eliminate measurable residual disease and to prevent post‐HSCT relapse. Veno‐occlusive disease/sinusoidal obstruction syndrome is a potential complication of InO treatment, particularly when followed by HSCT. Herein, the authors review the historical development and current status of InO, strategies for mitigating the risk of InO‐related veno‐occlusive disease/sinusoidal obstruction syndrome, and future directions for InO research and clinical use. Inotuzumab ozogamicin is approved to treat relapsed/refractory B‐cell acute lymphoblastic leukemia but is increasingly used in other treatment settings. The authors review the historical development and current status of inotuzumab ozogamicin in adult B‐cell acute lymphoblastic leukemia. [ABSTRACT FROM AUTHOR]

The role of hematopoietic cell transplantation (HCT) in adults with acute lymphoblastic leukemia (ALL) is reviewed and critically evaluated in this systematic evidence-based review. Specific criteria were used for searching the published literature and for grading the quality and strength of the evidence and the strength of the recommendations. A panel of ALL experts developed consensus on the treatment recommendations based on the evidence. Allogeneic HCT offers a survival benefit in selected patients with ALL, and this review summarizes the standard indications as well as the areas of controversy. There is now greater experience with pediatric-inspired chemotherapy regimens that has transformed upfront therapy for adult ALL, resulting in higher remission rates and overall survival. This in turn has increased the equipoise around decision making for ALL in first complete remission (CR1) when there is no measurable residual disease (MRD) at the end of induction and/or consolidation. Randomized studies are needed for adults with ALL to compare allogeneic HCT in CR1 with pediatric-inspired chemotherapy alone. Indications for transplantation in the evolving landscape of MRD assessments and novel targeted and immune therapeutics remain important areas of investigation. [ABSTRACT FROM AUTHOR]

Outcomes of relapsed adult acute lymphoblastic leukemia (ALL) have improved over time with the introduction of new therapies as well as better supportive care. However, there is still a need for easy-to-use and accurate prognostic tools for patients in first relapse. Whether complete response (CR) with incomplete count recovery (CRh) can be grouped with CR in relapsed ALL trials has not been formally studied. We analyzed 106 ALL patients at first relapse who were treated at three academic centers and achieved CR/CRh. White blood cell count at initial diagnosis and receiving hematopoietic cell transplant (HCT) were independent predictors of overall survival after relapse, while minimal residual disease (MRD) positivity and performance of HCT were predictors of relapse free survival (RFS). Patients who achieved MRD negativity and underwent HCT had the best outcomes. Our results suggest that MRD is a more powerful predictor of outcome than CRh. [ABSTRACT FROM AUTHOR]

The treatment of acute lymphoblastic leukemia (ALL) in adults remains challenging and novel therapies are needed. The antigen, CD19, is expressed by >90% of pre-B ALLs and represents an attractive therapeutic target. The bispecific T-cell-engaging antibody, blinatumomab, targets CD19 and has demonstrated encouraging results in minimal residual disease positive and relapsed/refractory pre-B ALL. In this review, we discuss in detail the mechanism of action and key pharmacologic aspects of blinatumomab. In addition, the preclinical studies, clinical studies and toxicities are summarized. [ABSTRACT FROM AUTHOR]

Chemotherapy alone cures only 25-45% of adult patients with acute lymphoblastic leukemia (ALL), making novel treatment agents and strategies desperately needed. The addition of monoclonal antibodies (rituximab, alemtuzumab, epratzumab) to chemotherapy has demonstrated encouraging results in patients with newly diagnosed and relapsed ALL. The anti-CD22 immunoconjugate, inotuzumab ozogamicin, and the anti-CD19 BiTE® antibody, blinatumomab, have demonstrated impressive single agent activity in patients with relapsed or refractory B-ALL. Early reports of chimeric antigen receptor therapies have been promising in patients with relapsed ALL. Other agents targeting NOTCH1, FLT3, the proteasome and DNA methylation are early in development. These new agents hope to improve the outcome of ALL therapy with less toxicity. The challenge going forward will be to find safe and effective combinations and determine where in the treatment schema these agents will be most effective in ALL therapy. [ABSTRACT FROM AUTHOR]

Philadelphia-like (Ph-like) acute lymphoblastic leukemia (ALL) is a high-risk subset of B-cell ALL characterized by high rates of treatment failure. Unsatisfactory outcomes with frontline therapy in adults with Ph-like ALL have been observed irrespective of the employed regimen, including modern pediatric-inspired regimens. Notably, Ph-like ALL is not an uncommon entity in adults, and it's prevalence extends to older patients with B-cell ALL. As the majority of Ph-like ALL cases harbor genetic alterations in kinases and/or cytokine receptors, the integration of tyrosine kinase inhibitors in newly diagnosed patients and poor early responders with Ph-like ALL has emerged as an area of active research with several ongoing clinical trials. Furthermore, the encouraging activity of novel therapies such as inotuzumab and blinatumomab in chemo-refractory B-cell ALL has promoted an interest in introducing these agents early in Ph-like ALL management, which may lead to improved cure rates with frontline therapies, sparing more adults from undergoing early allogeneic hematopoietic cell transplantation (HCT). Finally, the high relapse rate in patients with Ph-like ALL, does not necessary correlate with early minimal residual disease (MRD) response, raising the question of consolidation with allogenic HCT in all adults with Ph-like ALL in first complete remission irrespective of MRD response. [ABSTRACT FROM AUTHOR]