An open-label phase I/II study of cyclophosphamide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone in newly diagnosed myeloma.

We conducted a phase 1/2 trial evaluating the combination of cyclophosphamide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone (CVDD) for newly diagnosed multiple myeloma (MM). The primary objective of the phase 1 was to evaluate the safety and tolerability of maximum planned dose (MPD) and the phase 2 was to assess the overall response rate. Patients received 6-8 cycles of CVDD at four dose levels. There were no dose-limiting toxicities. The MPD was cyclophosphamide 750 mg/m(2) IV on day 1, bortezomib 1.3 mg/m(2) IV on days 1, 4, 8, 11, pegylated liposomal doxorubicin 30 mg/m(2) IV on day 4, and dexamethasone 20 mg orally on the day of and after bortezomib (21-d cycle). Forty-nine patients were treated at the MPD of which 22% had high-risk myeloma. The most common grade ≥3 toxicities included myelosuppression, infection, and fatigue. Overall response and complete response rates were 91% and 26% in standard-risk, and 100% and 58% in high-risk cohort, respectively. After a median follow-up of 34 months, the median progression-free survival was 31.3 months. The 2-yr overall survival was 91.1% in the standard-risk and 88.9% in the high-risk cohort, respectively. CVDD regimen was well tolerated and was highly active in newly diagnosed MM.

Sequence of novel agents in multiple myeloma: an instrumental variable analysis.

Lenalidomide and bortezomib have not been compared prospectively and are currently used in sequence for patients with multiple myeloma; however, it is unknown whether a sequence of administration could result in improved outcomes. We retrospectively reviewed electronic records of patients with multiple myeloma who had used both agents in sequence at our institution: 97 patients had lenalidomide first and 111 had bortezomib first. On multivariable analysis, the sequence of therapy was not associated with outcome. These findings were confirmed with instrumental variable analyses. Finally, use of bortezomib first was associated with improved survival for patients with baseline renal insufficiency.

Phase II study of CD4+-guided pentostatin lymphodepletion and pharmacokinetically targeted busulfan as conditioning for hematopoietic cell allografting.

One limitation of reduced-intensity preparative regimens is potential for graft failure. We have developed a regimen that targets CD4(+) lymphodepletion to ensure early and durable engraftment. The primary endpoint was achievement of ≥50% CD3(+) donor chimerism by day +28. Forty-two patients (median age, 53 years; range, 29 to 73 years) received pentostatin 4 mg/m(2) i.v. on days -28, -21, and -14 when the CD4(+) cell count was >100 cells/µL and on days -4 and -3 regardless of CD4(+) level. Rituximab 375 mg/m(2) was administered to patients with CD20(+) malignancies on days -21, -14, -7, +1, and +8. Busulfan 200 mg/m(2) i.v. was administered on days -4 and -2 at a dose to target a cumulative AUC dose of 16,000 (±10%) µmol·min/L. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus plus methotrexate in 86% of patients. Donors were matched-related (47%), matched unrelated (43%), or mismatched unrelated (10%). Chronic lymphocytic leukemia (45%) and follicular non-Hodgkin lymphoma (14%) were the most common diagnoses. Disease status at initiation of the preparative regimen was complete remission in 22%, partial response in 55%, and stable/progression in 24%. The median percent CD4(+) cell count decrease from baseline (day -28) was 52% to day -21, 66% to day -14, 62% to day -7, and 91% to day 0. At day +28, all 42 patients (100%) had ≥50% CD3(+) donor chimerism. No patient experienced graft failure. Overall response rate was 82% (complete remisson, 67%). The day +100 cumulative incidence of grade II-IV acute GVHD was 59% (grade III-IV acute GVHD, 19%), and the 2 year cumulative incidence of chronic GVHD was 69% (moderate/severe, 58%). Nonrelapse mortality was 2% at day +100 and 17% at 2 years. Two-year PFS was 55%, and OS was 68%. This regimen ensures durable engraftment, is effective against persistent disease, and results in relatively low mortality from causes other than relapse.

Melphalan Culprit or Confounder in Acute Encephalopathy during Autologous Hematopoietic Stem Cell Transplantation?

We report a case of a female patient with Durie-Salmon stage 3A/ISS stage I IgG kappa multiple myeloma (MM) who developed encephalopathy after high-dose melphalan and hematopoietic stem cell transplant (HSCT). The most common etiologies for encephalopathy such as infection, narcotic medications, metabolic-electrolyte disturbance, stroke, and central nervous system (CNS) hemorrhages were ruled out. The patient recovered from the altered mental status spontaneously. The possibilities of melphalan-induced encephalopathy versus critical-state delirium versus hypercytokinemia induce encephalopathy were contemplated.

Bortezomib salvage followed by a Phase I/II study of bortezomib plus high-dose melphalan and tandem autologous transplantation for patients with primary resistant myeloma.

We conducted a Phase 1/2 study of bortezomib administered in combination with high-dose melphalan followed by tandem autologous transplants in patients with primary resistant multiple myeloma. Thirty patients received two cycles of salvage bortezomib followed by stem cell mobilization with granulocyte colony-stimulating factor and harvest. Melphalan 100 mg/m(2) per day on two consecutive days was administered, immediately followed by one dose of bortezomib (dose escalation) and stem cell infusion. The median beta 2-microglobulin was 4·35 mg/l (range: 1·8-11·4); albumin was 37 g/l (range: 3·1-4·9); high-risk karyotypes were noted in 45% of patients. The maximum planned dose of bortezomib at 1·3 mg/m(2) was well tolerated and a formal maximum tolerated dose was not determined. The peak of best overall response (≥partial response) and complete response rates after tandem transplants were 84% and 36%, respectively. With a median follow-up of 48 months, the median progression-free survival was 15 [95% confidence interval (CI): 11-21] months and the median overall survival was 35 (95% CI: 22-43) months. Correlative studies demonstrated decreased expression of BRCA2 (P = 0·0072) and FANCF (P = 0·0458) mRNA following bortezomib treatment. Bortezomib combined with high-dose melphalan is a well-tolerated conditioning with some activity in patients with resistant myeloma.

Clinical outcomes of patients with plasma cell leukemia in the era of novel therapies and hematopoietic stem cell transplantation strategies: a single-institution experience.

BACKGROUND: PCL carries a poor prognosis and the optimal management remains unknown. PATIENTS AND METHODS: To evaluate the outcome of patients with PCL in the era of novel agents and innovative transplantation strategies, we conducted a review of patients with PCL who were treated at our institution from August 2003 to October 2009. Our primary endpoint was to determine overall survival, which was calculated from time of PCL diagnosis to death or last follow-up. Secondary endpoints included response rates and analyses regarding how the novel agents and presence of adverse cytogenetic analyses affected outcomes. RESULTS: We identified 25 patients with PCL (13 with primary PCL [pPCL], 12 with secondary PCL [sPCL]) from our institution. Eighteen patients received bortezomib-based regimens, 19 received high-dose melphalan followed by autologous hematopoietic stem cell transplantation (HCT), and 6 underwent allogeneic HCT. The median overall survival for all patients was 23.6 months. Bortezomib-treated patients had a median survival of 28.4 months vs. 4.0 months for the non-bortezomib-treated group (P < .001). CONCLUSIONS: Our analysis suggests that patients with PCL who were treated with bortezomib and/or allogeneic HCT had improved outcomes.

Human immunodeficiency virus (HIV)-negative plasmablastic lymphoma: a single institutional experience and literature review.

Plasmablastic lymphoma (PBL) is a rare aggressive B-cell lymphoproliferative disorder. HIV-negative PBL has not been extensively reported. Nine HIV-negative PBL patients evaluated at Moffitt Cancer Center were studied. Eight patients had extranodal diseases. All patients were treated with CHOP or hyper-CVAD. Responses were observed in 8 cases (7 complete, 1 partial responses). Four patients underwent consolidation with autologous hematopoietic stem cell transplant (HSCT) in first complete remission (CR1). At median follow-up of 23.9 months, 7 patients were alive and 5 were disease-free. Aggressive induction chemotherapy and consolidation with autologous HSCT in CR1 might be considered for patients with HIV-negative PBL.

Targeted IV busulfan and fludarabine followed by post-allogeneic hematopoietic cell transplantation rituximab demonstrate encouraging activity in CD20+ lymphoid malignancies without increased risk of infectious complications.

We examined pharmacokinetic-targeted IV busulfan (75-170 mg/m(2), with target AUC of 3500-6000 µmol min) and fludarabine (40 mg/m(2)) × 4 days with rituximab (t-IV Bu/Flu + rituximab) 375 mg/m(2) on days +1 and +8 followed by allogeneic hematopoietic cell transplantation in 19 patients (median age 56, range 35-68 years) with CD20+ lymphoid malignancies. Median time to neutrophil and platelet engraftment was 15 and 12 days. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 58% (95% confidence interval, CI 39-85%), and chronic GVHD was 50% (95% CI 28-88%). With a median follow up of 7 (range 1-31) months, overall response was observed in 15, and stable or progressive disease in 4. Overall survival at 1 year was 67%. Engraftment, chimerism, and infectious complications did not differ significantly from a contemporaneous non-rituximab containing comparator group. The addition of rituximab 375 mg/m(2) to t-IV Bu/Flu does not appear to adversely affect engraftment, donor chimerism, or increase the risk of infectious complications.

Patterns of use of vascular access devices in patients undergoing hematopoietic stem cell transplantation: results of an international survey.

INTRODUCTION: There is limited information regarding of use of vascular access devices (VAD) in patients undergoing hematopoietic stem cell transplantation (HSCT). The frequent use of VAD in HSCT and its potential to cause morbidity requires understanding of the general use of VAD in HSCT. MATERIALS AND METHODS: A World Wide Web-based 19-item questionnaire was designed to determine the patterns of use of VAD in patients undergoing HSCT. The questionnaire was sent via electronic mail to the directors of HSCT programs throughout the world. RESULTS: Of the 445 centers surveyed, 163 centers replied for a response rate of 37%. The most commonly used catheter for autologous peripheral blood stem cell (PBSC) harvest is the dual-lumen plasmapheresis/hemodialysis (62%). Of the institutions, 58% utilize the same catheter used for PBSC harvest to provide vascular access support during the transplant. Catheter-related blood stream infection (36%) and withdrawal occlusion (31%) were the most frequently encountered complications of VAD. Of the centers, 65% have established criteria for VAD removal when infection is suspected and 48% when occlusion is suspected. DISCUSSION: Our study demonstrated that there are similarities in the utilization of VAD but also wide differences in the standard procedures for the insertion and care of VAD in the transplant setting. More comprehensive studies are needed to assess the use of central venous catheters in transplant recipients. Important areas for future research include the impact of VAD utilization on the quality of life of transplant recipients and the final consequences of VAD complications.

Phase I and pharmacokinetic study of sequences of the rebeccamycin analogue NSC 655649 and cisplatin in patients with advanced solid tumors.

PURPOSE: To evaluate the feasibility of administering NSC 655649, a water-soluble rebeccamycin analogue that inhibits both topoisomerases I and II, in combination with cisplatin (CDDP) in adults with solid malignancies. Major toxicologic and pharmacologic differences between the two sequences of drug administration were also assessed. EXPERIMENTAL DESIGN: NSC 655649 was administered as a 60-minute i.v. infusion; CDDP was given i.v. before or after NSC 655649 on day 1. Each patient was treated with alternating drug sequences every 3 weeks; doses of each drug were escalated in separate cohorts of new patients. Sequential dose escalation of NSC 655649 or CDDP resulted in three dosage permutations of NSC 655649/CDDP: 440/50, 550/50, and 440/75 mg/m2. After the maximum tolerated dose level was determined, the feasibility of using granulocyte colony-stimulating factor to permit further dose escalation was explored. RESULTS: Twenty patients were treated with 70 courses of NSC 655649/CDDP. Myelosuppression was the principal toxicity. The incidence of severe neutropenia, often associated with severe thrombocytopenia, was unacceptably high in minimally pretreated patients at the NSC 655649/CDDP dose level of 550/50 mg/m2 without and with granulocyte colony-stimulating factor. Major pharmacokinetic interactions between NSC 655649 and CDDP were not apparent. No relevant sequence-dependent differences in toxicity or pharmacokinetic variables occurred. Three patients had partial responses. CONCLUSIONS: NSC 655649 and CDDP were well tolerated by minimally pretreated subjects at 440 and 50 mg/m2, respectively. Neither pharmacokinetic interactions between the agents nor sequence-dependent toxicologic or pharmacokinetic effects were apparent. The tolerance and preliminary activity observed with this combination suggest that disease-directed evaluations of the regimen are warranted.