Mounzer Agha

Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study

This multicenter phase 1/2 trial investigated the combination of bendamustine, lenalidomide, and dexamethasone in repeating 4-week cycles as treatment for relapsed refractory multiple myeloma (MM). Phase 1 established maximum tolerated dose (MTD). Phase 2 assessed overall response rate at the MTD. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A total of 29 evaluable patients were enrolled. Median age was 63 years (range, 38-80 years). Median number of prior therapies was 3 (range, 1-6). MTD was bendamustine 75 mg/m(2) (days 1 and 2), lenalidomide 10 mg (days 1-21), and dexamethasone 40 mg (weekly) of a 28-day cycle. Partial response rate was 52%, with very good partial response achieved in 24%, and minimal response in an additional 24% of patients. Median follow-up was 13 months; median OS has not been reached. One-year OS is 93% (95% confidence interval [CI], 59%-99%). Median PFS is 6.1 months (95% CI, 3.7-9.4 months) with one-year PFS of 20% (95% CI, 6%-41%). Grade 3/4 adverse events included neutropenia, thrombocytopenia, anemia, hyperglycemia, and fatigue. This first phase 1/2 trial testing bendamustine, lenalidomide, and dexamethasone as treatment of relapsed refractory MM was feasible and highly active. This study is registered at www.clinicaltrials.gov as #NCT01042704.

Gemtuzumab therapy for isolated extramedullary AML relapse following allogeneic stem-cell transplant.

Background A 19-year-old male with primary refractory acute myeloid leukemia received salvage therapy with mitoxantrone and cytarabine combination. He received consolidation therapy 3 months later with a matched-unrelated-donor stem-cell transplant. The disease relapsed in the bone marrow (BM) 9 months after the initial stem-cell transplant, and was successfully treated by repeat transplant from the same donor. Ten months following repeat transplant, the patient presented with an increasing number of extramedullary sites of biopsy-proven disease relapse (i.e. cranial and peripheral nerves, tongue, abdominal wall and chest wall). Repeated biopsy of the BM and chimera study showed no morphologic evidence of leukemic infiltrate with 100% donor-cell population.Investigations Physical examination, complete blood count, BM biopsy, flow cytometry, cytogenetic analysis, chimera study, tongue biopsy, abdominal-wall biopsy, cytology and immunohistochemistry, CT scan of the chest, abdomen and pelvis, MRI of the brain, and cerebrospinal fluid analysis.Diagnosis Isolated extramedullary relapse of acute myeloid leukemia after stem-cell transplant.Management Primary leukemia treatment with idarubicin, cytarabine, etoposide, dexamethasone, tioguanine on protocol and salvage therapy with mitoxantrone and cytarabine combination for primary refractory disease. A matched-unrelated-donor stem-cell transplant for consolidation and donor-lymphocyte infusions were performed, followed by repeat unrelated-donor transplant for leukemia relapse in the marrow, radiation therapy and gemtuzumab ozogamicin for multiple sites of extramedullary leukemia relapse.

Risk factors for acquisition of multidrug-resistant Acinetobacter baumannii among cancer patients

BACKGROUND Data regarding multidrug-resistant (MDR) Acinetobacter baumannii infections among cancer patients are limited. METHODS We conducted a case-control study to investigate the risk factors for acquisition of MDR A baumannii and the outcomes among cancer patients. Cases were inpatients with malignancy who had MDR A baumannii from any cultures between 2008 and 2011. Controls were inpatients with malignancy but no MDR A baumannii. RESULTS A total of 31 case patients were matched with 62 control patients. Hematologic malignancy (P = .036), need for dialysis (P = .01), admission for other reasons except elective surgery (P = .03), transfer from other health care facilities (P = .02), prolonged intensive care unit stay (P = .004), mechanical ventilation (P < .001), pressor use (P = .001), tube feeding (P < .001), transfusion (P = .009), and prior antimicrobial use (P < .001) were identified as significant risk factors in univariate analysis. Need for dialysis (odds ratio [OR], 18.23; P = .04) and prolonged intensive care unit stay (OR, 19.28; P = .01) remained significant in multivariate analysis. Lengths of stay were 28 days for the case patients and 10 days for the control patients (P = .001). The 90-day mortality rates were 41.9% and 29.0%, respectively (P = .20). CONCLUSIONS Acquisition of MDR A baumannii among cancer patients appears to be associated with general nosocomial infection risk factors rather than underlying malignancies.

Gemtuzumab ozogamicin as first-line treatment in patients aged 70 years or older with acute myeloid leukemia

Elderly patients with acute myeloid leukemia (AML) are generally unable to withstand the rigors of intensive induction chemotherapy and its attendant complications. Gemtuzumab ozogamicin (GO) is an immunoconjugate that had demonstrated activity in recurrent AML.

De novo acute myeloid leukemia with Philadelphia chromosome (BCR-ABL) and inversion 16 (CBFB-MYH11): report of two cases and review of the literature.

Cytogenetic and molecular studies play a major role in myeloid disease subclassification and risk stratification. The 2008 World Health Organization (WHO) classification [1] recognizes several diseasedefining recurrent genetic abnormalities in acute myeloid leukemia (AML), one of which is inversion 16(p13q22) or t(16;16), which fuses the CBFB gene to the MYH11 gene, and is characteristically associated with myelomonocytic differentiation, abnormal eosinophils, and a good prognosis [2]. The hallmark of chronic myelogenous leukemia (CML) is the Philadelphia chromosome (Ph), formed as a result of the BCR–ABL translocation; however, the BCR–ABL abnormality is not specific to CML and may also be seen in precursor lymphoid neoplasms and rare cases of de novo AML [3,4]. Coexistence of Ph(BCR–ABL1) and inv(16)(CBFB–MYH11) is extremely uncommon, with only 30 cases reported in the literature. The majority of these cases represent the blast phase of CML (CML-BP), and have shown an aggressive clinical course with rapidly progressive disease and resistance to chemotherapy [5,6]. In contrast, the few reports regarding de novo Phþ inv(16)þ AML have suggested a more favorable prognosis [6–14]. We report the clinicopathologic features of two new cases of de novo AML with the Philadelphia chromosome and inversion 16 and review the literature. Case one is a 30-year-old female who presented with leukocytosis (white blood cell count [WBC] 47.96 10/L) with circulating blasts (7%), monocytosis (54%), and thrombocytopenia (1146 10/L). The bone marrow was nearly 100% cellular and normal marrow elements were replaced by a prominent myelomonocytic infiltrate, with manual differential counts showing increased blasts (9%), monocytic cells (28%), and eosinophils (18%) with abnormal, basophilic granulation. Flow cytometric analysis confirmed increased CD14þ monocytic cells and an aberrant myeloblast population, which was CD347CD117þCD33þ. Classical cytogenetic studies showed the following complex karyotype: 46,XX, t(9;22;17;19)(q34; q11.2; q25; p13.1), inv(16) (p13q22)[19]. Quantitative real-time (RT)-polymerase chain reaction (PCR) studies performed on the peripheral blood and bone marrow confirmed the presence of a BCR–ABL fusion transcript at the minor breakpoint cluster region (p190). Therapy included hydroxyurea, allopurinol, imatinib (600 mg/day), and high dose chemotherapy with busulfan and cyclophosphamide, followed by an allogeneic stem cell transplant. Although a complete clinical, cytogenetic, and molecular remission was initially attained, the patient relapsed 29, 53, 70, and 80 months after the initial diagnosis. The first three relapses were responsive to cytarabine-based

Leukapheresis in patients newly diagnosed with acute myeloid leukemia

Hyperleukocytosis is present in 5 to 20 percent of patients with newly diagnosed acute myeloid leukemia (AML). The management of hyperleukocytosis, when symptoms of leukostasis occur, includes intensive supportive care and interventions for rapid cytoreduction. Leukapheresis is a rapid and effective means of cytoreduction and has been used in AML patients. In the current study, we evaluated the outcomes of 68 newly diagnosed AML patients that underwent leukapheresis and the effects of leukapheresis on various laboratory parameters. A total of 127 leukapheresis cycles were performed. The median number of leukapheresis cycles was 2 (range, 1-8). The overall survival for all patients was 4.2 months (95% CI 1.2-9.7 months). The median overall survival for patients who achieved complete remission after induction chemotherapy was significantly higher (19.1 months [95% CI 12.1-41.8 months]) than patients that did not achieve complete remission (0.46 months [95% CI 0.33-0.99 months]). Stepwise logistic regression demonstrated that elevated number of peripheral blasts, low platelet count and elevated bilirubin at AML diagnosis were predictive of death within a week. Leukapheresis was effective in reducing the peripheral blood leukocytes and leukemia blasts and was a safe procedure with regard to organ function, coagulation parameters, red blood cells and platelet count. The high initial response rates in newly diagnosed AML patients fit to receive intensive chemotherapy suggest that leukapheresis could be beneficial in reducing the complications associated with hyperleukocytosis until systemic intensive chemotherapy commences.

IV pentamidine for primary PJP prophylaxis in adults undergoing allogeneic hematopoietic progenitor cell transplant.

IV pentamidine for primary PJP prophylaxis in adults undergoing allogeneic hematopoietic progenitor cell transplant

Fludarabine and cytarabine in patients with acute myeloid leukemia refractory to two different courses of front-line chemotherapy

The most effective regimen for acute myeloid leukemia (AML) patients who do not achieve complete remission (CR) after two different courses of front-line chemotherapy has not been established. We therefore evaluated the efficacy, toxicity, and prognostic factors for achieving CR following treatment with fludarabine and cytarabine in 25 newly diagnosed AML patients who did not respond to initial therapy with idarubicin and cytarabine followed by mitoxantrone and etoposide. CR was achieved in 32% of patients; in 55% of patients with intermediate-risk karyotype and in 14% with unfavorable-risk. Eight percent died of infectious complications. Median duration of overall survival was 6.6 months (95% CI 3.4 months to ∞); 3.4 months (95% CI 0.8-8.6 months) for patients with an unfavorable-risk karyotype and 18.1 months (95% CI 5.0 months to ∞) with an intermediate-risk karyotype (p=0.02). Our data suggest that poor-risk karyotype patients are unlikely to benefit from third course treatment with fludarabine-cytarabine, and that this regimen merits further investigation in AML patients with good or intermediate-risk karyotype that have persistent leukemia after two courses of front-line chemotherapy.

Mitoxantrone and etoposide in patients with newly diagnosed acute myeloid leukemia with persistent leukemia after a course of therapy with cytarabine and idarubicin.

The most effective regimen for patients with acute myeloid leukemia (AML) who do not achieve complete remission (CR) after one course of cytarabine and an anthracycline has not been extensively studied. We evaluated restrospectively the efficacy, toxicity, and prognostic factors for the achievement of CR following mitoxantrone and etoposide in 74 patients with newly diagnosed AML who did not respond to one course of therapy with cytarabine and idarubicin. CR was achieved in 39% of patients; 14% died of infectious complications; no grade 3 or 4 hepatic toxicities were observed. Median duration of overall survival was 9.0 months (95% CI 5.8–14.9 months). The median duration of relapse-free survival was 11.0 months (95% CI: 9.0–19.3 months). A lower CR rate was associated with unfavorable risk status at diagnosis and higher percent blasts. Our data suggest that the combination of etoposide and mitoxantrone is an effective second-course therapy in patients with newly diagnosed AML.

Peri‐transplant Clostridium difficile infections in patients undergoing allogeneic hematopoietic progenitor cell transplant

Clostridium difficile infections (CDI) remain the leading cause of infectious diarrhea among hospitalized patients in this country. Patients with hematologic malignancies, especially those who undergo hematopoietic progenitor cell transplants are particularly at risk for developing CDI. One hundred and forty seven consecutive allogeneic hematopoietic progenitor cell transplants were analyzed for peri‐transplant Clostridium difficile infections (PT‐CDI). Sixteen patients (11%) developed PT‐CDI (Median time = 7 days after transplant). The probability for developing PT‐CDI during the peri‐transplant period was 12.3%. History of CDI was strongly associated with the development of PT‐CDI (P = 0.008) (OR = 5.48) (P = 0.017). These patients also developed PT‐CDI much earlier than in those without a history (median 1 day vs. 8 days, P = 0.03). The probability for developing PT‐CDI for those with a history was 39%. There was a trend toward significance (P = 0.065) between matched related donor grafts and the development of PT‐CDI (OR = 0.245) (P = 0.08). Age, sex, diagnosis, transplant preparative regimens, Graft‐versus‐host disease (GVHD) prophylaxis, grade 3/4 acute GVHD, or use of antimicrobials within 8 weeks of transplant were not associated with PT‐CDI. Non‐CDI‐related deaths occurred in one patient in the PT‐CDI group and nine in the group without PT‐CDI. In the remaining 139 patients, the length of hospital stay for those with PT‐CDI was significantly longer than those without (mean 27 days vs. 22 days; P = 0.02). Am. J. Hematol. 91:291–294, 2016.