Aberrant expression of CD13 identifies a subgroup of standard-risk adult acute lymphoblastic leukemia with inferior survival.

BACKGROUND: The standard-risk (SR) subgroup of acute lymphoblastic leukemia in adults (aALL) is a heterogeneous category, with a 20% to 40% relapse rate and a wide range of relapse-free survival (RFS) and overall survival (OS). There is a need to identify at the outset those patients with SR-aALL who are likely to have shorter RFS and OS, so they can be treated more aggressively. PATIENTS AND METHODS: Flow cytometric data of 81 patients with SR-aALL treated with a standardized protocol were retrospectively analyzed. Thirty-two patients (40%) relapsed; the median RFS and OS were 12.5 months (range, 1-136 months) and 30 months (range, 3-235 months), respectively. Twenty-six patients survived ≥ 48 months. RESULTS: Expression of myeloid antigen CD13, using the conventional ≥ 20% threshold and a lower ≥ 5% threshold, was seen in 17 (29%) of 59 and 29 (49%) of 59 patients, respectively, whereas dual expression of CD13 and CD33 was seen in 8 patients. CD13 positivity at ≥ 20% and ≥ 5% threshold was associated with a shorter RFS (P = .0158 and P < .0001, respectively) and OS (P = .0072 and P < .0001, respectively). Dual expression of CD13 (at ≥ 5% or ≥ 20% threshold) and CD33 was associated with inferior OS (P = .0038 and P = .0032, respectively) and RFS (P = .0705 and P = .2516, respectively). For ≥ 20% and ≥ 5% threshold of positivity, 16 of 42 and 28 of 42 who survived < 48 months were positive, compared with 1 of 17 and 1 of 17 who survived ≥ 48 months (P = .0133 and P < .0001, respectively). CONCLUSION: Aberrant expression of CD13 in ≥ 5% of blasts of patients with SR-aALL is an adverse prognostic factor, delineating a subgroup of patients with SR-aALL that should be considered for more aggressive treatment.

Normal karyotype CALLA-positive adult pre-B ALL: dismal outcome with chemotherapy for patients with loss/gain of ABL1 and/or BCR FISH signals.

BACKGROUND: Diagnostic karyotype and molecular studies represent the most powerful prognostic indicators in acute myeloid leukemia and provide the framework for risk stratification. Risk stratification in ALL has also a vital role in predicting outcome and identifying patients at higher risk of relapse with multiagent chemotherapy, but the role of diagnostic karyotype and molecular markers in adult ALL is limited to few well recognized cytogenetic abnormalities. PATIENTS AND METHODS: We report a case series of 6 adult ALL patients with a characteristic molecular abnormality that have done poorly with chemotherapy. Between April 2004 and November 2009, 72 adult ALL patients (Pre-B-cell 61; T-cell 11) were referred to and treated at the Leukemia/BMT Program of BC in Vancouver, Canada. FISH for BCR-ABL fusion was positive in 12 of 61 Pre-B cell ALL patients. An additional 6 patients were negative for this typical fusion but had FISH abnormalities related to BCR and/or ABL1. RESULTS: In this report, we describe the clinical and hematopathologic characteristics of these 6 patients and their poor outcome. We review the literature where only 2 similar cases with normal karyotype Pre-B ALL and associated FISH BCR/ABL1 numerical abnormalities were found. CONCLUSION: We recommend screening all adult pre-B ALL patients with normal karyotype for this clonal abnormality and suggest classifying these ALL patients into the high-risk category.

Allogeneic haematopoietic stem cell transplantation for chronic lymphocytic leukaemia: outcome in a 20-year cohort.

The curative potential of allogeneic haematopoietic stem cell transplant (allo HSCT) in chronic lymphocytic leukaemia CLL is established, with a demonstrated role for graft-versus-leukaemia and less certainty for other factors in determining outcome. The first two decades of CLL patients proceeding to allo HSCT at the Leukaemia/Bone Marrow Transplant Program of British Columbia (n = 49 consecutive, 1991-2009) were studied to clarify factors predicting outcome. The donor was related in 29 (59%) and unrelated in 20 (41%). Conditioning was reduced-intensity in 27 (55%) and myeloablative in 22 (45%). Thirty-one of 49 patients survive with median follow-up of 5 years (0·2-15). Cumulative incidence of non-relapse mortality; complete remission (CR); clearance of fluorescence in situ hybridization (FISH) abnormality and progression at 10 years was 36%; 69%; 55% and 22%. Overall survival (OS) was 63% at 2 years; 55% at 5 years and beyond. Factors predicting OS (P value by log rank <0·05) were: comorbidity index <3, FISH rank (Dohner) and 17p deletion, alemtuzumab pre-HSCT, achievement of CR post-HSCT, donor chimerism >90%, clearance of FISH abnormality post-HSCT and absence of high-grade (3-4) graft-versus-host disease. Results from this province-wide, two-decade cohort demonstrated that a substantial proportion of patients with high-risk CLL become long term disease-free survivors.

Long-term follow-up of patients with chronic myeloid leukemia in chronic phase developing sudden blast phase on imatinib therapy.

Sudden blast phase (SBP) is a rare event that occurs in an unpredictable fashion amongst patients with chronic myeloid leukemia (CML) who otherwise appear to be responding satisfactorily to imatinib (IM) treatment. We investigated the incidence, clinical characteristics, treatment outcome and long-term follow-up of 213 patients with chronic phase CML treated with IM according to the European LeukemiaNet guidelines. Nine patients, eight of whom received IM as first-line therapy, developed SBP (4.2% of the total). They tended to have low or intermediate risk Sokal scores at diagnosis, a predominance of the lymphoid phenotype and a short interval from "optimal" response to the development of BP. Five of the nine patients with SBP are alive in complete molecular remission; however, all of them underwent allogeneic hematopoietic stem cell transplant. The cumulative incidence of SBP for the patients who received IM as first-line therapy was 5.9% and the 2-year overall survival of the nine patients who developed SBP was 56%. Despite the improved outcome for patients with SBP receiving tyrosine kinase inhibitors (TKIs) and transplant, many of these patients are not salvaged with these therapies. This illustrates the need to develop predictive models to identify patients early whose response to TKI therapy will not be durable and hopefully prevent the transformation to advanced disease.

Response to tyrosine kinase inhibitor therapy in patients with chronic myelogenous leukemia relapsing in chronic and advanced phase following allogeneic hematopoietic stem cell transplantation.

Tyrosine kinase inhibitors (TKI) have been used to treat relapse of chronic myelogenous leukemia (CML) after allogeneic stem cell transplant (HSCT), with responses seen predominantly in chronic phase (CP) patients. This study aimed to analyze the response to TKI therapy and overall survival for patients relapsing predominantly in advanced phase. We retrospectively reviewed 22 patients treated with imatinib (n=20) and/or dasatinib (n=6) for relapsed CML after HSCT; 8 patients were in CP, and 14 patients had advanced disease. Seven patients also received donor lymphocyte infusions. Hematologic, cytogenetic, and molecular responses were analyzed. Nineteen patients (86%) achieved complete hematologic response (CHR), 17 patients (77%) achieved complete cytogenetic response (CCR), and 14 patients (64%) achieved complete molecular response (CMR). In advanced phase patients, 11 (79%) achieved CHR, 10 (71%) CCR, and 8 (57%) achieved CMR. Grade 3 or 4 cytopenias occurred in 10 cases. With median follow-up of 31.5 months from relapse, 14 (64%) patients remain alive, 13 in CMR. In multivariate analysis, the achievement of CMR was significantly correlated with OS with an odds ratio of 20.5 (95% confidence interval 2.3-182) P=.007. TKI therapy is capable of inducing durable molecular responses for CML relapsing after HSCT, both in chronic and advanced phases. The achievement of CMR appears to be crucial in providing long-term disease control for these patients.

Current status of allogeneic hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria.

Treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) has been traditionally empirical, primarily aiming at ameliorating symptoms or treating complications resulting from the disease. Novel therapies such as eculizumab result in stabilization of hemoglobin levels and improvement in quality of life, but does not cure PNH. Nonrandomized studies suggest that long-term remissions are achievable when using myeloablative or nonmyeloablative/reduced-intensity (NMT/RIC) allogeneic hematopoietic stem cell transplantation (HSCT) as treatment for PNH. Nevertheless, patients with previous life-threatening complications from PNH may be more appropriately treated with an NMT/RIC regimen, rather than a myeloablative approach, because of the increased transplant mortality associated with the latter. The decision to perform an allogeneic HSCT (allo-HSCT) should weigh disease prognosis, by incorporating known adverse prognostic factors such as previous history of thrombosis and/or evolution to pancytopenia, among others, against the risk of transplant-related complications. Selection of the appropriate candidate and, equally important, the right time to perform an allo-HCT are important questions that need to be answered in the context of large prospective randomized trials.

IPSS poor-risk karyotype as a predictor of outcome for patients with myelodysplastic syndrome following myeloablative stem cell transplantation.

The optimal therapy for myelodysplastic syndrome (MDS) is allogeneic bone marrow (BM) or blood (BSC) stem cell transplantation (SCT), although outcomes are limited by nonrelapse mortality (NRM) and relapse. A retrospective review was performed of 156 patients who underwent SCT (114 BM, 42 BSC) for MDS or secondary acute myelogenous leukemia (sAML) at our institution. Fifty-five patients remain in continuous complete remission: 35 BM recipients and 20 BSC recipients (median follow-up 139 and 89 months, respectively). Estimated 7-year event-free survival (EFS), NRM, and risk of relapse (ROR) are 33% (95% confidence intervals [CI] 25%-43%), 42% (CI 33%-51%), and 25% (CI 17%-33%) for the BM cohort and 45% (CI 32%-64%, P= .07), 32% (CI 18%-47%, P= .15), and 23% (CI 11%-37%, P= .79) for the BSC cohort. Multivariate analysis showed IPSS poor-risk cytogenetics (P< .001), time from diagnosis to SCT (P< .001), FAB subgroup (P= .001), recipients not in complete remission (CR1) at SCT (P= .005), and the development of acute graft-versus-host disease (aGVHD) (P= .04) were all predictive of an inferior EFS. The FAB subgroup (P= .002), poor-risk karyotype (P= .004), and non-CR1 status also correlated with ROR in multivariate analysis. EFS for poor-risk karyotype patients was superior after receiving BSC compared to BM (39% versus 6%, P< .001). SCT outcomes in MDS/sAML are strongly associated with the IPSS cytogenetic risk group, although the use of BSC in poor-risk karyotype patients may lead to a more favorable long-term EFS.

Allogeneic hematopoietic cell transplantation for adult Philadelphia-positive acute lymphoblastic leukemia in the era of tyrosine kinase inhibitors.

Allogeneic hematopoietic cell transplantation in first complete remission (CR1) is considered the standard of care, and the only established therapy that offers a possibility of cure for patients with Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Unfortunately, a number of patients, with suitable HLA-matched donors, are unable to receive an allograft because they fail to respond, or relapse shortly after induction chemotherapy. Incorporating imatinib during the induction/consolidation phase is facilitating a higher number of potentially curative allografts by improving both remission rates and/or the durability of responses in patients with Ph+ ALL. Imatinib and other tyrosine kinase inhibitors are also improving outcomes in elderly patients with Ph+ ALL, ineligible for allografting, when combined with glucocorticoids, and/or conventional chemotherapy. The addition of imatinib or other tyrosine kinase inhibitors to the therapeutic armamentarium of Ph+ ALL is reshaping the treatment algorithm and improving prognosis of this dreadful disease.

Hematopoietic cell transplantation in acute promyelocytic leukemia: a comprehensive review.

The past three decades have brought major therapeutic advances in the management of acute promyelocytic leukemia. The current state-of-the-art induction treatment with all-trans retinoic acid in combination with anthracycline-based chemotherapy results in long-lasting remissions and cure in up to 70% of newly diagnosed patients. Unfortunately, treatment failure still occurs in one-third of patients. When disease relapses, patients can achieve subsequent remissions with arsenic trioxide, all-trans retinoic acid with or without chemotherapy, or other therapies. Patients achieving molecular remissions after salvage therapy are generally considered candidates for high-dose chemotherapy and autologous hematopoietic cell transplantation as a postconsolidation strategy. On the other hand, patients with evidence of persistent hematologic or molecular disease after salvage therapy could be offered allogeneic hematopoietic transplantation if a suitable HLA-donor is identified and the patient's overall performance and clinical condition are permissible. We hereby provide a comprehensive review and analysis of published clinical trials that evaluate the role of hematopoietic cell transplantation across different stages of acute promyelocytic leukemia.