Zartash Gul

Hematopoietic Stem Cell Transplantation for Multiple Myeloma: Guidelines from the American Society for Blood and Marrow Transplantation.

Therapeutic strategies for multiple myeloma (MM) have changed dramatically over the past decade. Thus, the role of hematopoietic stem cell transplantation (HCT) must be considered in the context of this evolution. In this evidence-based review, we have critically analyzed the data from the most recent clinical trials to better understand how to incorporate HCT and when HCT is indicated. We have provided our recommendations based on strength of evidence with the knowledge that ongoing clinical trials make this a dynamic field. Within this document, we discuss the decision to proceed with autologous HCT, factors to consider before proceeding to HCT, the role of tandem autologous HCT, post-HCT maintenance therapy, and the role of allogeneic HCT for patients with MM.

High Incidence of Severe Acute Graft-Versus-Host Disease with Tacrolimus and Mycophenolate Mofetil in a Large Cohort of Related and Unrelated Allogeneic Transplantation Patients

Both acute and chronic graft-versus-host disease (GVHD) are major causes of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT). The optimal pharmacological regimen for GVHD prophylaxis is unclear, but combinations of a calcineurin inhibitor (cyclosporin or tacrolimus [Tac]) and an antimetabolite (methotrexate or mycophenolate mofetil [MMF]) are typically used. We retrospectively evaluated the clinical outcomes of 414 consecutive patients who underwent AHSCT from sibling (SD) or unrelated donors (UD) with Tac/MMF combination, between January 2005 and August 2010. The median follow-up was 60 months. Less than one third of the patients received a reduced-intensity chemoregimen. The incidence of grades III and IV acute GVHD was 22.3% and 36.5% in SD and UD groups, respectively (P = .0007). The incidence of chronic GVHD was 47.1% and 52.7% in the SD and UD groups, respectively. Nonrelapse mortality (NRM) at 60 months was 33.3% and 46.5% in the SD and UD groups, respectively (P = .0016). The incidence of relapse was 22.4% for UD and 28.8% for SD. Five-year overall survival was 43% and 34% in the SD and UD groups, respectively (P = .0183). GVHD was the leading cause of death for the entire cohort. Multivariable analysis showed that 8/8 HLA match, patients age < 60, and low-risk disease were associated with better survival. The use of Tac/MMF for GVHD prophylaxis was associated with a relatively high incidence of severe acute GVHD and NRM in AHSCT from sibling and unrelated donors.

Blinatumomab May Induce Graft Versus Host Leukemia in Patients with Pre-B ALL Relapsing After Hematopoietic Stem Cell Transplant

Blinatumomab, a bispecific T‐cell engager monoclonal antibody used to manage Philadelphia chromosome‐negative relapsed or refractory B‐cell precursor acute lymphoblastic leukemia (ALL) can be used to treat patients by inducing graft versus leukemia reaction post allogeneic hematopoietic stem cell transplantation, a feature which it was post allogeneic bone marrow transplantation, a feature which this drug was not aimed to do.

Phase I trial of bortezomib during maintenance phase after high dose melphalan and autologous stem cell transplantation in patients with multiple myeloma.

Abstract We enrolled 15 patients in this phase I dose de-escalation trial. Twelve patients are evaluable. The primary objective was to determine the safest and best tolerated maintenance dosing (MD) of bortezomib (B). The secondary endpoints were to evaluate complete response (CR), overall response (OR) and response duration. All patients receiving autologous stem cell transplant (ASCT) were eligible and registered between D+30 to D+120 after ASCT. A maximum number of 8 cycles of B was planned. Two evaluable patients in level (L) 1 received therapeutic dose of B 1·3 mg/m2 intravenously on days (D) 1, 4, 8, and 11 in a 21 day cycle. Both these patients experienced dose limiting toxicities (DLTs). Four evaluable patients were then enrolled in dose L2 utilizing B 1·3 mg/m2 on D 1, 4, 8, and 11 in a 28 day cycle. Two patients in L2 developed DLTs. Six evaluable patients were thereafter enrolled in L3 utilizing B 1 mg/m2 on D 1, 8, and 15 in a 28 day cycle. Median 8 cycles of B were administered (2–8). No DLTs were observed in L3. The median duration of follow up for the entire cohort is 33 months (12–62). The median duration of response in L3 is 29·1 months (12–33). We conclude that B 1 mg/m2 administered intravenously and may be subcutaneously on D 1, 8, and 15 in a 28 day cycle is the best tolerated MD and can be safely given beginning around D+100 post-ASCT.

Low blood lymphocyte count at 30 days post transplant predicts worse acute GVHD and survival but not relapse in a large retrospective cohort

Multiple reports have shown that low absolute lymphocyte count at day 30 (ALC30) after allogeneic hematopoietic SCT (AHSCT) is associated with higher risk of disease relapse and worse OS. However, these reports included heterogeneous populations with different grafts and GVHD prophylaxis. Therefore, we retrospectively evaluated the association of ALC30 with transplant outcomes in a cohort of 381 consecutive patients who underwent AHSCT between 2005 and 2010 and received T-replete PBSC grafts and Tacrolimus/Mycophenolate combination as GVHD prophylaxis. Median follow-up was 57 months. Lower ALC30 (⩽400 × 106/L) was associated with lower OS and increased nonrelapse mortality (NRM) for the whole cohort as well as for recipients of SD and UD grafts separately. Lower ALC30 was associated with more severe acute GVHD (aGVHD; III–IV) for the entire cohort as well as for the SD and UD groups. No association was found between lower ALC30 and relapse. Pretransplant factors associated with lower ALC30 were: unrelated donors; HLA mismatch; older donors; lower recipient age; and lower CD34+ cell dose. In this large retrospective study, ALC30⩽400 × 106/L was associated with worse OS, increased NRM and severe aGVHD.

Cytomegalovirus reactivation is associated with a lower rate of early relapse in myeloid malignancies independent of in-vivo T cell depletion strategy

The association between cytomegalovirus (CMV) reactivation and relapse risk has not been evaluated in relation to T cell depletion strategies. We evaluated 93 patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) and analyzed the association between T cell depletion strategies with the cumulative incidence of relapse and CMV reactivation. A total of 33% of patients who received ATG vs. 34% who received alemtuzumab developed CMV reactivation. The cumulative incidence of relapse was 3% at 1year and 20% at 3 years in patients with CMV reactivation vs. 30% at 1year and 38% at 3 years in patients without CMV reactivation (p=0.02). When analyzed separately, this effect persisted in the myeloid, but not the lymphoid group. There was a numerical trend towards increased non-relapse mortality (NRM) in patients with CMV reactivation, especially in the myeloid group. The choice of T cell depleting agent and the rate of CMV reactivation were not associated with different overall survival (OS) rates. These results suggest that the choice of T cell depletion strategy may have similar effects on rates of CMV reactivation, disease relapse, and survival. Further studies examining these variables in patients not exposed to in-vivo T cell depleting agents may be of interest.

Short-term cardiac toxicity of autologous hematopoietic stem cell transplant for multiple myeloma

Th e last two decades have seen tremendous progress in the treatment of multiple myeloma, including the use of high-dose melphalan (HDM) with autologous hematopoietic stem cell transplant (auto-HCT) and the availability of various novel agents [1]. Th e incidence of cardiotoxicity after HDM is not known, even though there have been case reports of cardiac arrhythmias with HDM [2,3]. In this study, we evaluated the incidence of cardiac adverse events (AEs) in 325 patients within 30 days of undergoing auto-HCT using HDM at M. D. Anderson Cancer Center for multiple myeloma between January 2006 and December 2009. We excluded 78 patients with concurrent immunoglobulin light chain amyloidosis (AL). In the group who experienced cardiac AEs, melphalan doses of 200 mg/m 2 (19 patients) and 180 mg/m 2 (one patient) were used. Similarly, melphalan doses of 200 mg/m 2 (215 patients), 180 mg/m 2 (six patients), 160 mg/m 2 (one patient) and 140 mg/m 2 (two patients) were used in the group without cardiac AEs. In two patients without cardiac AEs the melphalan dose was missing. All patients received granulocyte colony stimulating factor (G-CSF), 5 μ g/kg/ day from day 1 until the absolute neutrophil count (ANC) was 0.5 109/L for 2 consecutive days, as per departmental guidelines. Supportive care measures, including blood product transfusion and electrolyte and weight management were done as per institutional guidelines. Cardiac toxicity was defi ned as any cardiac AE reported from the day of administration of melphalan to day 30 after auto-HCT. Th ese cardiac AEs included congestive heart failure (CHF), arrhythmias, ischemic chest pain and sudden cardiac death. CHF was defi ned as any structural or functional cardiac disorder that impaired the ability of the ventricles to fi ll or eject blood, with associated symptoms of fatigue, dyspnea and fl uid retention. Sudden cardiac death was defi ned as cessation of cardiac activity leading to unresponsiveness and demise of the patient. Ischemic chest pain was defi ned as typical substernal chest pain that was precipitated by exertion, radiating to the jaw and the inner aspect of the arms or shoulders, and relieved by nitroglycerin. Prior cardiac history was defi ned as a history of coronary artery disease, arrhythmias, valvular heart disease or cardiac light-chain amyloidosis before auto-HCT. Th e primary endpoint of the study was to evaluate the incidence of cardiac AEs after HDM and auto-HCT. We also evaluated the variables that could aff ect cardiac AEs. Th ese variables included a prior history of hypertension, diabetes, tobacco smoking, prior chemotherapy, interval between diagnosis and auto-HCT, cardiac biomarkers (troponin and brain natriuretic peptide [BNP]) and echocardiogram. Cardiac biomarkers are routinely collected as a part of pre-transplant evaluation.

Post-Transplantation Management Strategies

Relapse is an overwhelmingly difficult and tragic event for patients suffering from hematologic malignancies that have been treated with bone marrow transplantation. More often than not, treatment options are fairly limited in each disease. Selecting the appropriate maintenance therapy gives a chance to delay or avoid these recurrences entirely. Although no perfect combination of drugs has yet been established as a mainstay maintenance therapy post-transplant, the authors here discuss the most effective and safest drugs available for different diseases.

Influence of rituximab and central nervous system directed prophylactic therapy on central nervous system relapse in high-risk diffuse large B-cell lymphoma

Background: Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) although rare, can be devastating. Conflicting reports have been published regarding the protective effect of systemic rituximab therapy and likely reduction in incidence of CNS relapse in post-rituximab era. Methods: We retrospectively identified all the DLBCL patients at our institute between 2004 and 2014 who received systemic rituximab-based chemo-therapy at initial presentation. Patients were categorized into two groups, “standard risk” with no risk factors and “high risk” with one or more of the following risk factors, elevated lactate dehydrogenase (LDH) (above the institute normal), international prognostic index (IPI) ≥3, involvement of testis, breast, bone, kidneys, adrenal gland, retroperitoneal lymph nodes, para-meninges, and bone marrow. Descriptive statistics were used to analyze inci-dence of CNS relapse, patient and disease characteristics. Historically reported incidence rates were used for comparison. Results: A total of 122 patients received rituximab-based therapy at the initial diagnosis; 73 patients (60%) qualified for standard risk; 49 patients (40%) met the criteria for “high risk” based on the above definition. Standard risk group received no CNS directed prophylaxis and none of these patients had CNS relapse. Thirty-one of 49 (63%) “high risk” patients received CNS prophylaxis, mainly intrathecal (IT) methotrexate. Five patients (4.0%) developed CNS relapse in the entire study population. Percentage of patients developed CNS relapse in high-risk patients was 10.2% (5/49). Median time to relapse was 8.76 months and median survival after CNS relapse was 9.16 months. Four out of five patients who developed CNS relapse received prophylaxis with IT. Conclusions: CNS relapse continued to be a rare but devas-tating complication in post rituximab era, however our study confirms that majority of the DLBCL patients do not need CNS directed therapy. Current CNS directed therapies are probably inadequate to prevent CNS relapse in high risk DLBCL patients, therefore further research to develop better agents is needed in this area.

Concomitant Renal Cell Carcinoma and Hematologic Malignancy in Immunosuppressed Patients

Objectives: Treatment of a renal mass in patients with hematologic malignancy or on immunosuppression can be complex and is not well defined. Surgical excision or thermal ablation of renal mass is generally recommended in view of concern for tumor progression in immunosuppressed patients. We report our management decision experience in patients and literature review on concomitant renal and hematologic malignancy. Materials and Methods: A retrospective medical record review of patients with renal cell carcinoma (RCC) and a hematologic malignancy over 3 years at our University Hospital was performed. Data were collected including patients demographics, renal tumor and hematologic malignancy characteristics (stage, pathologic subtype, time of diagnosis, treatment type and prognosis). Surgical and medical management of each malignancy was reviewed and perioperative and overall outcomes are reported. Results: In total, 6 patients were identified with RCC and a hematologic malignancy of which 4 were on immunosuppressive therapy. A total of 5 patients had leukemia and 1 patient had multiple myeloma. Most kidney tumors were stage I, 83%; and 80% were Fuhrman grade II. There was equal distribution of clear cell and papillary‐type RCC. All but 1 patient had undergone nephron‐sparing surgery. Overall, 50% of our patients died within 1 year after renal surgery for pT1a tumors from causes that are unrelated to renal cancer. Conclusions: Our small cohort showed significant mortality in patients with hematologic malignancy on immunosuppression, who had their renal mass treated with surgical excision or thermal ablation. However, this mortality was not secondary to surgical procedure itself. The prognosis of the hematologic malignancy might dictate the management of RCC.