Autologous hematopoietic cell transplantation with augmented BCNU-regimens is effective treatment for recurrent or refractory Hodgkin lymphoma (HL), however BCNU-related toxicity and disease recurrence remain challenges. We designed a conditioning regimen with gemcitabine in combination with vinorelbine in an effort to reduce the BCNU dose and toxicity without compromising efficacy. In this phase I/II dose escalation study, the gemcitabine maximum tolerated dose (MTD) was determined at 1250 mg/m2, and a total of 92 patients were treated at this dose to establish safety and efficacy. The primary endpoint was the incidence of BCNU-related toxicity. Secondary endpoints included 2-year freedom from progression (FFP), event-free survival (EFS), and overall survival (OS). Sixty-eight patients (74%) had one or more previously defined adverse risk factors for transplant (stage IV at relapse, B symptoms at relapse, greater than minimal disease pre-transplant). The incidence of BCNU-related toxicity was 15% (95% confidence interval, 9% to 24%). Only 2% of patients had a documented reduction in diffusing capacity of 20% or greater. With a median follow-up of 29 months, the FFP at 2 years was 71% and the OS at 2 years was 83%. Two-year FFP was 96%, 72%, 67%, and 14% for patients with 0 (n=24), 1 (n=37), 2 (n=23), or 3 (n=8) risk factors, respectively. Regression analysis identified PET status pre-transplant and B symptoms at relapse as significant prognostic factors for FFP. This new transplant regimen for HL resulted in decreased BCNU toxicity with encouraging FFP and OS. A prospective, risk-modeled comparison of this new combination with other conditioning regimens is warranted.

Background: B cells are implicated in the pathophysiology of chronic GVHD. We hypothesize that prophylactic anti-B cell therapy delivered two months after reduced intensity conditioning (RIC) transplantation would prevent or reduce chronic GVHD incidence from the historical 50%. Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) were the target diseases as they are B cell malignancies with clear allogeneic GVL benefit. Methods: CLL and MCL patients were conditioned with total lymphoid irradiation (TLI) 80 cGy in 10 fractions, d-11 to d-1 and anti-thymocyte globulin (ATG) 1.5mg/kg/day, d-11 to d-7 (total 7.5mg/kg). PBPC were infused on day 0. Primary GVHD prophylaxis was cyclosporine (CSA) on d-3 with taper by 6 months, and MMF from day 0 until d28 for related donors, d100 for unrelated donors. Rituximab (375 mg/m2/week ×4) was infused on days 56, 63, 70, and 77 post-transplant. Results: 36 patients accrued to the study (median age 57, range 31–66 yrs), with 34 patients completing the 4 rituximab infusions. All 22 CLL patients were high risk (fludarabinerefractory, unmutated VH-IgG, or P53 deletion). The 14 MCL patients included 4 patients in PR and 10 patients in CR status at transplant. Median follow-up is 20 months. Twenty patients had sibling donors; 16, unrelated donors. Median CD34 cell dose was 7.5 CD34/kg. All patients had donor cell engraftment except for one patient who had graft failure with stable autologous recovery. Full donor chimerism (PB CD3>95%) was achieved in 14 out of 31 patients (45%) by day 90. However, all but 5 patients had achieved full donor chimerism at 1 year. The incidence of grade 2–4 acute GVHD was 6%. The incidence of chronic GVHD was 18%. Day 100 NRM was 0% and 1-year NRM was 3%. Ten relapses have occurred (5 CLL, 5 MCL). Estimated FFP and OS at 2 years for CLL patients is 82%(CI +/−16%) and 73% (CI +/−33%), respectively; for MCL patients, 64% and 68%, respectively Full donor chimerism was associated with persistent disease remission. Twelve of 19 VHIg mutated CLL patients have achieved minimal residual disease (MRD) by quantitative allele-specific oligonucleotide-IgH PCR (ASO-Q-PCR). DLI was given to 5 CLL patients and 1 MCL who had relapsed and had not achieved full donor chimerism.. There were no infusional toxicities with rituximab. Transient rituximab related neutropenia occurred in 10 patients d100–150. Post-transplant infections included influenza B, RSV, fungal sinusitis, pseudomonas, klebsiella infection, VZV reactivation, and one PTLD before day 56 rituximab. All recovered Of 22 patients at risk for CMV reactivation, 10 reactivated ( range 4 to 56 days post-HCT). Therefore, rituximab did not contribute to the CMV reactivation or increase infection incidence. Conclusion: Prophylactic rituximab infusion post RIC transplantation is well tolerated, provides safe donor B cell depletion without detrimental effect on engraftment or infection incidence, and is associated with a low incidence of chronic GVHD while maintaining GVL. A randomized trial of rituximab prophylaxis after allogeneic HCT is warranted.

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Background: High dose chemotherapy and autologous hematopoietic cell transplantation (AHCT) is the most effective treatment for recurrent and refractory Hodgkin lymphoma (HL). Disease recurrence is still a major cause of treatment failure. Augmented BCNU-regimens are reported to have good outcomes but greater pulmonary toxicity. A novel transplant regimen incorporating gemcitabine and vinorelbine, active drugs in HL different from alkylating agents, was tested to establish the maximum tolerated dose (MTD) of gemcitabine and to assess safety and efficacy at the MTD. Methods: In this phase I/II study, dose escalation was performed with gemcitabine in combination with vinorelbine followed by BCNU at reduced dose, etoposide (VP-16), cyclophosphamide (CY) and AHCT. The first 7 patients had dose escalation of gemcitabine before determining the MTD at 1250 mg/m2 on the basis of elevated liver transaminases and a symptom complex of fever, headache, and skin toxicity. For phase II, a total of 92 patients with recurrent or refractory HL have been treated at the MTD to establish safety and efficacy. The regimen consists of gemcitabine 1250 mg/m2 IV at 10 mg/min and vinorelbine 30 mg/m2 on day-13 and day-8, BCNU 10 mg/kg on day-6, VP-16 60 mg/kg on day-4, CY 100 mg/kg on day-2. Regimen-related toxicity, freedom from progression (FFP) and overall survival (OS) were endpoints of the trial. Results: 70 patients were high risk (based on stage IV disease at relapse, failure to achieve minimal disease, or B symptoms at relapse) and 22 patients were low risk (having no risk features). Median age was 33 years. Median follow-up is 2 years (.26–6.8 years). Median time to neutrophil engraftment was 10 days. Regimen-related toxicities of grade 3 skin rash, fever, headache and liver transaminase elevations were transient. Remarkable was the reduction in incidence of systemic steroid-requiring pulmonary toxicity <100 days post-transplant to 15.2% (14 of 92 patients treated at the MTD), as compared to our standard regimen incidence of 35%. Also encouraging is the OS at 2 years for the entire group of 81% (+/−9%) and FFP at 2 years of 71%(+−11%). By risk factors, FFP at 2 years was 95%(+−10%), 75%(+−14%), 64%(+−22%), and 19%(+−31%) for patients with 0, 1, 2, or 3 risk factors. These results compare favorably to the historical FFP of 41% for patients with one or more of these same risk factors (Horning 1997). In the current study, having 1 or 2 risk factors resulted in similar FFP with the new regimen (p=.46) and significantly improved FFP as compared to patients with 3 risk factors (1 vs 3, p<.001; 2 vs 3, p=.004)- see figure. Conclusions: This novel transplant regimen for HL has decreased incidence of pulmonary toxicity compared with augmented BCNU-regimens and is associated with encouraging OS and FFP, even in the high risk groups. Figure Figure