Guru Subramanian Guru Murthy

Trends in survival outcomes of B-lineage acute lymphoblastic leukemia in elderly patients: analysis of Surveillance, Epidemiology, and End Results database

B-lineage acute lymphoblastic leukemia (B-ALL) in the elderly population is generally considered to have a poor prognosis. It is unclear whether their survival has improved in the current era. Using the Surveillance, Epidemiology, and End Results database, we selected 717 elderly patients (age ≥ 60) with B-ALL diagnosed between 1992 and 2011. Overall survival (OS) was compared based on their period of diagnosis and age. Patients in the age group 60–69 had an improvement in OS over time, both 1-year OS (49.4% in 2002–2011 vs. 33.1% in 1992–2001) and 5-year OS (20.4% in 2002–2011 vs. 8.1% in 1992–2001, p = 0.002). Patients ≥ 70 years had no significant improvement in 1-year OS or 5-year OS (5-year OS 5.5% in 1992–2001 vs. 9.7% in 2002–2011, p = 0.326). Hence, there are discrepancies in the improvement of OS among elderly patients with B-ALL. Further focus of research in elderly patients with B-ALL is needed to improve their outcome.

Incidence and survival outcomes of chronic myelomonocytic leukemia in the United States

Abstract Chronic myelomonocytic leukemia (CMML) is an aggressive neoplasm with sparse data on outcomes at a population level. Using Surveillance Epidemiology and End Results (SEER) database, we identified 2238 patients with CMML diagnosed in the period 2003–2013. We found that the disease incidence was significantly higher with advancing age and lower in females, Blacks, and Asian/pacific islanders. Median OS declined significantly with increasing age (age 20–39 – 25 months, age 40–59 – 20 months, age 60–79 – 18 months, and age ≥80 – 11 months, p < .01), but did not vary by gender or race. Median OS has improved in the period 2007–2013 as compared with 2003–2006 (17 months vs. 14 months, p < .01). In spite of advances in CMML biology and therapeutics, in general, the survival of CMML patients remains dismal. More effective therapies are needed to improve the outcomes of CMML.

Clinicopathologic features and management of blastoid variant of mantle cell lymphoma.

The blastoid variant of mantle cell lymphoma (MCL), which accounts for less than one-third of MCL, may arise de novo or as a transformation from the classical form of MCL. Blastoid variant, which predominantly involves men in their sixth decade, has frequent extranodal involvement (40–60%), stage IV disease (up to 85%) and central nervous system (CNS) involvement. Diagnosis relies on morphological features and is challenging. Immunophenotyping may display CD23 and CD10 positivity and CD5 negativity in a subset. Genetic analysis demonstrates an increased number of complex genetic alterations. Blastoid variant responds poorly to conventional chemotherapy and has a short duration of response. Although the optimal therapy remains to be established, CNS prophylaxis and the use of aggressive immunochemotherapy followed by autologous stem cell transplant may prolong the remission rate and survival. Further studies are crucial to expand our understanding of this disease entity and improve the clinical outcome.

Autologous Hematopoietic Cell Transplantation in Patients With Multiple Myeloma: Effect of Age

Background In the novel and pre–novel agent era, high‐dose therapy, followed by autologous hematopoietic cell transplantation (AHCT), has been shown to prolong survival in patients with multiple myeloma (MM) in randomized trials. However, these trials only included patients aged ≤ 65 years. Given that the median age at diagnosis is 66 years, it is important to know the outcomes of AHCT in older patients. Similarly, definite outcomes of AHCT in very young patients (aged < 50 years) are also lacking because they represent a very small proportion of patients in clinical trials. Materials and Methods We analyzed a consecutive cohort of patients with MM receiving AHCT from 2000 to 2015 in 2 different age groups, older (> 70 years) and younger (≤ 50 years), and compared the outcomes. The primary objectives were to assess overall survival, progression‐free survival (PFS), and nonrelapse mortality in these 2 groups. Results Of the 191 patients, 86 were young (age ≤ 50 years) and 105 were old (age > 70 years). The younger patients had better performance status and a lower comorbidity index, and most of the older patients had received a melphalan dose of 140 to 180 mg/m2. The median follow‐up period for the young group was 33 months (range, 2‐164 months) compared with 22.5 months (range, 3‐133 months) in the old group (P = .02). The PFS rate at 1 year was 60% (95% confidence interval [CI], 46%‐72%) for the young group and 58% (95% CI, 45%‐69%) for the old group. The overall survival rate at 1 year was 92% (95% CI, 84%‐96%) for the young group and 85% (95% CI, 76%‐91%) for the old group. On multivariate analysis, age did not have any effect on survival (P = .82); however, the patients with high‐risk cytogenetics (hazard ratio [HR], 2.2; 95% CI, 1.06‐4.6; P = .04) had worse overall mortality. High‐risk cytogenetics (HR, 1.2; 95% CI, 1.1‐3.5; P = .004) and no disease response or progressive disease at transplantation (HR, 5.0; 95% CI, 1.8‐13.5; P = .02) were significantly associated with worse PFS. Conclusion Age should not be a limiting factor in considering the modality of AHCT. However, younger patients might also benefit from additional novel treatment approaches in the setting of clinical trials, given their similar outcomes with the older patients in our study. Micro‐Abstract Autologous hematopoietic cell transplantation has been shown to prolong survival in patients with multiple myeloma; however, adequate data are lacking for patients aged > 70 years and < 50 years. We retrospectively analyzed and compared the outcomes of patients between the 2 age groups (> 70 vs. ≤ 50 years). Our study showed comparable outcomes between these 2 age groups.

Reactivation of Pulmonary Tuberculosis following Treatment of Myelofibrosis with Ruxolitinib

Ruxolitinib is widely in use for treatment of myeloproliferative disorders. It causes inhibition of the Janus kinase (JAK) signal transducer and activation of transcription (STAT) pathway, which plays a key role in the underlying pathophysiology of myeloproliferative diseases. We describe a case of reactivation pulmonary tuberculosis in a retired physician while on treatment with ruxolitinib. We also review the literature on opportunistic infections following use of ruxolitinib. Our case highlights the importance of screening for latent tuberculosis in patients from highly endemic areas prior to start of therapy with ruxolitinib.

New Oral Anticoagulants for the Management of Heparin Induced Thrombocytopenia: A Focused Literature Review.

OBJECTIVE Drugs currently in use for the management of heparin-induced thrombocytopenia (HIT) have their limitations. Several new oral anticoagulants (NOACs) such as dabigatran, rivaroxaban and apixaban may offer attractive therapy options for HIT. Although the clinical data are sparse on this topic, we have summarized the available clinical data, discussed pertinent in-vitro studies and provided the rational and advantages of using NOACs in patients with suspected or confirmed HIT. We have also reviewed the safety and efficacy of these NOACs in patients with HIT based on published literature. METHODS We reviewed all suspected or confirmed HIT cases treated with NOACs and indexed in English language in MEDLINE and EMBASE by July 2015. The bibliography of each relevant article was searched for additional reports. In-vitro studies and other pertinent literature were briefly discussed. RESULTS A total of 36 HIT patients were treated with the following NOACs: rivaroxaban (50%), dabigatran (36%) and apixaban (14%). Sixty-one percent of patients received argatroban bolus before NOACs and 3% received rivaroxaban after a lack of response with three-day course of fondaparinux. Three percent (n=1) received rivaroxaban after the patient responded to intravenous immunoglobulin for 2 days, following a lack of response to fondaparinux and bilvalirudin. In another 3% (n=1), prophylactic dose of rivaroxaban was used for 21 days and then changed to dabigatran because of persistent thrombocytopenia. All cases responded with early signs of clinical improvement and increase in platelet counts. A follow-up after a median 47 days (range 4- 450) reported no bleeding or thrombotic complications. CONCLUSION In this review, all patients with HIT treated with NOACs responded without any bleeding or thrombotic complication. Although the argatroban bolus might have contributed to a response in some patients, response to NOAC alone in other patients and in-vitro studies provide a proof of principle that NOACs can be effective in the management of HIT. Additionally, properties such as rapid onset of action, oral administration, ease of use and a lack of need for monitoring make these drugs attractive options for HIT. However, given several limitations of prior reports, further confirmation of the results are desirable.

Relapse of Hodgkin lymphoma after autologous transplantation: Time to rethink treatment?

Relapse of Hodgkin lymphoma after autologous hematopoietic cell transplantation (autologous HCT) is a major therapeutic challenge. Its management, at least in younger patients, traditionally involves salvage chemotherapy aiming to achieve disease remission followed by consolidation with allogeneic hematopoietic cell transplantation (allogeneic HCT) in eligible patients. The efficacy of salvage therapy is variable and newer combination chemotherapy regimens have improved the outcomes. Factors such as shorter time to relapse after autologous HCT and poor performance status have been identified as predictors of poor outcome. Newer agents such as immunoconjugate brentuximab vedotin, checkpoint inhibitors (e.g., pembrolizumab, nivolumab), lenalidomide, and everolimus are available for the treatment of patients relapsing after autologous HCT. With the availability of reduced intensity conditioning allogeneic HCT, more patients are eligible for this therapy with lesser toxicity and better efficacy due to graft versus lymphoma effects. Alternative donor sources such as haploidentical stem cell transplantation and umbilical cord blood transplantation are expanding this procedure to patients without HLA-matched donors. However, strategies aimed at reduction of disease relapse after reduced intensity conditioning allogeneic HCT are needed to improve the outcomes of this treatment. This review summarizes the current data on salvage chemotherapy and HCT strategies used to treat patients with relapsed Hodgkin lymphoma after prior autologous HCT.

Acute Leukemia of Ambiguous Lineage in Elderly Patients – Analysis of Survival Using Surveillance Epidemiology and End Results-Medicare Database

&NA; We used the Surveillance Epidemiology and End Results‐Medicare database to study the overall survival and treatment pattern of elderly patients with acute leukemia of ambiguous lineage in the United States. Overall survival of this leukemia remains poor, but is improved significantly with chemotherapy. Background: Acute leukemia of ambiguous lineage (ALAL) is a rare leukemia with sparse data availability about the survival and management strategies in elderly patients. Methods: We used the Surveillance Epidemiology and End Results (SEER)‐Medicare database to describe the overall survival (OS) and treatment pattern of elderly patients (age > 65 years) with ALAL. OS analysis was done using the Kaplan‐Meier method, and its determinants were analyzed using the Cox proportional hazard regression method with a significant P < .05. Results: We included 705 patients with ALAL and a median age of 80 years. The 2‐year OS was 16.4% for patients aged 66 to 70 years, 8.1% for patients aged 71 to 75 years, 5.5% for patients aged 76 to 80 years, and 3.7% for patients aged > 80 years (P < .01). Two‐year OS did not significantly vary by race or gender. Among the study cohort, 151 patients received chemotherapy. Two‐year OS was 17% in the chemotherapy group and 3% in the no‐chemotherapy group (P < .001). On multivariate analysis, age less than 80 years (Age 66‐70 years: hazard ratio [HR]; 0.66, 95% confidence interval [CI], 0.52‐0.85; age 71‐75 years: HR, 0.80; 95% CI, 0.65‐0.99; age 76‐80 years: HR, 0.80; 95% CI, 0.66‐0.98; P = .004) and chemotherapy (HR, 0.51; 95% CI, 0.42‐0.62; P = .001) significantly reduced the hazard for mortality. Conclusion: Our study suggests that the OS of elderly patients with ALAL remains poor. Although treatment improved the OS, only 21.5% of patients received therapy. The optimal choice of therapy needs to be determined by prospective studies.

Recipient Immune Modulation with Atorvastatin for Acute Graft-versus-Host Disease Prophylaxis after Allogeneic Transplantation

Atorvastatin administration to both the donors and recipients of matched related donor (MRD) allogeneic hematopoietic cell transplantation (allo-HCT) as acute graft-versus-host disease (GVHD) prophylaxis has been shown to be safe and effective. However, its efficacy as acute GVHD prophylaxis when given only to allo-HCT recipients is unknown. We conducted a phase II study to evaluate the safety and efficacy of atorvastatin-based acute GVHD prophylaxis given only to the recipients of MRD (n = 30) or matched unrelated donor (MUD) (n = 39) allo-HCT, enrolled in 2 separate cohorts. Atorvastatin (40 mg/day) was administered along with standard GVHD prophylaxis consisting of tacrolimus and methotrexate. All patients were evaluable for acute GVHD. The cumulative incidences of grade II to IV acute GVHD at day +100 in the MRD and MUD cohorts were 9.9% (95% confidence interval [CI], 0 to 20%) and 29.6% (95% CI,15.6% to 43.6%), respectively. The cumulative incidences of grade III and IV acute GVHD at day +100 in the MRD and MUD cohorts were 3.4% (95% CI, 0 to 9.7%) and 18.3% (95% CI, 6.3% to 30.4%), respectively. The corresponding rates of moderate/severe chronic GVHD at 1 year were 28.1% (95% CI, 11% to 45.2%) and 38.9% (95% CI, 20.9% to 57%), respectively. In the MRD cohort, the 1-year nonrelapse mortality, relapse rate, progression-free survival, and overall survival were 6.7% (95% CI, 0 to 15.4%), 43.3% (95% CI, 24.9% to 61.7%), 50% (95% CI, 32.1% to 67.9%), and 66.7% (95% CI, 49.8% to 83.6%), respectively. The respective figures for the MUD cohort were 10.3% (95% CI, 8% to 19.7%), 20.5% (95% CI, 7.9% to 33.1%), 69.2% (95% CI, 54.7% to 83.7%), and 79.5% (95% CI, 66.8% to 92.2%), respectively. No grade 4 toxicities attributable to atorvastatin were seen. In conclusion, the addition of atorvastatin to standard GVHD prophylaxis in only the recipients of MRD and MUD allo-HCT appears to be feasible and safe. The preliminary efficacy seen here warrants confirmation in randomized trials.

Haploidentical Hematopoietic Cell Transplantation in Lymphomas

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative salvage treatment for patients with lymphoproliferative disorders (LPDs). In the United States, it is estimated that about 19,790 patients with non-Hodgkin lymphoma (NHL) and 1150 patients with Hodgkin lymphoma died in the calendar year of 2015. Progressive disease is a leading cause of mortality in patients with lymphomas. Although allo-HCT appears to be an attractive treatment option for patients with advanced lymphomas, its widespread application is often limited by factors such as HLA-matched donor availability and the risk of post-transplant morbidity. Haploidentical HCT (haplo-HCT) expands the allo-HCT strategy to patients without an available fully HLA-matched adult donor, while novel haplo-HCT techniques have improved the safety of this approach. Historically, in the haploidentical setting, severe graft-versus-host disease (GvHD), higher risk of non-relapse mortality (NRM), disease relapse, and delayed immune reconstitution were challenges despite extensive in vivo or ex vivo T-cell depletion aimed at reduced graft rejection and GvHD risk. More recently, several Asian centers have reported favorable outcomes of haplo-HCT utilizing T-cell replete grafts with intensive immunosuppression using antithymocyte globulin (ATG). A different strategy of T-cell replete haplo-HCT being increasingly used involves the administration of high-dose post-transplantation cyclophosphamide (PTCy), which mitigates the risk of GvHD by targeting alloreactive T-cells rapidly proliferating early after HLA-mismatched transplant while sparing regulatory T-cells and hematopoietic progenitor cells. The near universal and ease of haploidentical donor availability have led to a rapid adoption of this strategy in patients with LPDs.