Clinical activity of a new regimen combining gemcitabine and alemtuzumab in high‐risk relapsed/refractory chronic lymphocytic leukemia patients

Optimal treatment strategies are lacking in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Gemcitabine has shown activity and acceptable safety profile in B‐cell lymphomas. We present a retrospective case review of gemcitabine and alemtuzumab, every 21 d (for up to six courses) in 27 community‐based patients with high‐risk R/R CLL. Median age was 70 yr (44–83 yr), 55% patients had Binet stage C, deletion 17p (del(17p)) and/or deletion 11q (del(11q)) were found in 65% and 27%, bulky disease in 55.5%, and fludarabine‐refractoriness in 48% of cases, respectively. Overall response rate was 63% (29.6% clinical CR and 33.4% PR). At a median follow‐up of 31 months, median PFS and OS were 15.4 and 24 months. In multivariate analysis, median OS is influenced by prior lines of treatment = 3 and bulky disease. Combination of alemtuzumab and gemcitabine appears to be an active, easy to administrate treatment in routine practice, high‐risk R/R CLL patients.     

An open-label, pilot study of fludarabine, cyclophosphamide, and alemtuzumab in relapsed/refractory patients with B-cell chronic lymphocytic leukemia

Although combination regimens have improved outcomes over monotherapy in chronic lymphocytic leukemia (CLL), patients eventually relapse. Combined fludarabine, cyclophosphamide, and monoclonal anti-CD52 antibody alemtuzumab (FCC) provided synergistic cytotoxicity with effective clearing of minimal residual disease. This phase 2 study determined FCC efficacy and safety in relapsed/refractory CD52(+) B-CLL after ≥ 1 line of treatment. From January 2005 through June 2008, up to 6 courses of oral fludarabine 40 mg/m2 per day, oral cyclophosphamide 250 mg/m2 per day, and subcutaneous alemtuzumab (Mab-Campath) 10 mg (increased to 20 mg after first 10-patient cohort) were administered days 1 to 3 every 28 days. The primary objective was overall response rate (ORR); secondary objectives included response duration, time to disease progression, and safety and tolerability. ORR was 67% in 43 patients; 30% achieved complete response. ORR significantly improved with 1 versus ≥ 2 prior therapies (P = .018), and without versus with previous monoclonal antibody treatment (P = .003). Median progression-free survival was 24.4 months, not reached in patients achieving complete response. Median overall survival was 33.6 months. Myelosuppression was the most common adverse event, with a low percentage of cytomegalovirus reactivations and manageable infections. However, close vigilance of opportunistic infections is warranted. FCC provides effective immunotherapy in relapsed/refractory CLL, including in patients with poor-risk prognostic factors.     

Alemtuzumab in chronic lymphocytic leukemia: final results of a large observational multicenter study in mostly pretreated patients

This retrospective study evaluated the benefit of alemtuzumab monotherapy in unselected patients with advanced B-cell chronic lymphocytic leukemia (CLL) and prolymphocytic leukemia (B-PLL) to definitely describe the impact of this antibody in clinical routine use. Data were collected from 208 consecutive, mainly pretreated, patients with CLL (n?=?202), and B-PLL (n?=?6) who had received alemtuzumab. Response, progression-free survival (PFS), and overall survival (OS) in various settings were assessed, and toxicities were documented. In these routine patients, a comparably low cumulative dose of alemtuzumab (median, 403 mg) was applied. In CLL, overall response rate was 32 %, and various pre-therapeutic parameters were predictive for inferior response, among them, the prior administration of ≥3 therapy lines (P?<?0.001), refractoriness to fludarabine (P?=?0.002), and bulky lymphadenopathy (P?=?0.003). PFS and OS after start of alemtuzumab were 6.2 and 21.0 months, respectively. Bulky lymphadenopathy was the prominent risk factor for both inferior PFS (P?<?0.001) and OS (P?=?0.002). In B-PLL, four patients experienced a fatal outcome, whereas two patients had some benefit with alemtuzumab. The main adverse effects were CMV reactivation (20 %) and a broad spectrum of infections, which together were the main reasons for treatment interruption and/or premature termination. In conclusion, alemtuzumab administered even at low dose levels was effective but overall considerably toxic in routine CLL patients. We emphasize that alemtuzumab remains an important therapeutic option in subsets of CLL patients.     

Platinum and high‐dose cytarabine‐based regimens are efficient in ultra high/high‐risk chronic lymphocytic leukemia and Richter's syndrome: results of a French retrospective multicenter study

Ultra high‐risk chronic lymphocytic leukemia (CLL) and Richter's syndrome (RS) usually display a poor prognosis. Platinum and cytarabine‐based regimens have not been evaluated in large cohorts of patients with CLL or RS. This retrospective study was aimed to assess the efficacy of these regimens in 75 patients with relapsed/refractory (R/R) CLL or RS. Forty‐seven patients had R/R CLL (including 36 ultra high‐risk CLL) and 28 had RS. Median age was 62 years (range, 18–79 years). Median number of previous therapies was 3 (range, 1–7), including fludarabine‐based regimens (75%) and alemtuzumab (32%), and 61% of patients were refractory to their last treatment. Deletions of chromosomes 17p and 11q were found in 40% and 39% of cases, respectively. The overall response rates were 60% with 24% complete response (CR) in CLL, and 43% with 25% CR in RS. The median progression‐free survival and overall survival were 11 and 14.6 months, respectively. Fludarabine refractoriness and 17p deletion were not associated with a poorer outcome. The only factors predicting shorter survival were performance status ≥2 (P = 0.04) and albumin level <3.5 g/dL (P = 0.0004). Toxicities were mainly myelosuppression and infectious complications. Platinum and high‐dose cytarabine‐based regimens provide high response rates in high‐risk CLL and in RS. However, these results will be challenged by the new arriving agents at least in non‐transformed CLL.     

An Italian retrospective study on the routine clinical use of low-dose alemtuzumab in relapsed/refractory chronic lymphocytic leukaemia patients

Low‐dose alemtuzumab has shown a favourable toxicity profile coupled with good results in terms of efficacy in relapsed/refractory chronic lymphocytic leukaemia (CLL). We conducted a multicentre retrospective study on the routine clinical use of low‐dose alemtuzumab in this patient setting. One hundred and eight relapsed/refractory CLL patients from 11 Italian centres were included in the analysis. All patients had an Eastern Cooperative Oncology Group performance status ≤2 and the majority (84%) had adenopathies <5cm. Low‐dose alemtuzumab was defined as a total weekly dose ≤45 mg and a cumulative dose ≤600 mg given for up to 18 weeks. The overall response rate was 56% (22% complete remissions). After a median follow‐up of 42·2 months, the median overall survival and progression‐free survival were 39·0 and 19·4 months, respectively. In univariate analysis, response was inversely associated with lymph node (P = 0·01) and spleen (P = 0·02) size, fludarabine‐refractoriness (P = 0·01) and del(11q) (P = 0·009). Advanced age and del(17p) were not associated with a worse outcome. Cumulative dose of alemtuzumab was not associated to response. Toxicities were usually mild and manageable; severe infections occurred in seven patients (7%) during therapy. This retrospective analysis confirms that low‐dose alemtuzumab is a valid and currently used therapeutic option for the treatment of relapsed/refractory CLL.     

Ofatumumab added to dexamethasone in patients with relapsed or refractory chronic lymphocytic leukemia: Results from a phase II study

The treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) remains a challenging clinical issue. An important treatment option is the use of high‐dose corticosteroids. The purpose of this clinical trial was to determine the efficacy and toxicity of an ofatumumab–dexamethasone (O‐Dex) combination in relapsed or refractory CLL. The trial was an open‐label, multicenter, nonrandomized, Phase II study. The O‐Dex regimen consisted of intravenous ofatumumab (Cycle 1: 300 mg on day 1, 2,000 mg on days 8, 15, and 22; Cycles 2–6: 1,000 mg on days 1, 8, 15, and 22) and oral dexamethasone (40 mg on days 1–4 and 15–18; Cycles 1–6). The O‐Dex regimen was given until best response, or a maximum of six cycles. Thirty‐three patients (pts) were recruited. Twenty‐four (73%) pts completed at least three cycles of therapy. The remaining nine pts were prematurely discontinued owing to Grade 3/4 infections (seven pts), disease progression (one pt), or uncontrollable diabetes mellitus (one pt). Overall response rates/complete remissions (ORR/CR) were achieved in 22/5 pts (67/15%). The median progression‐free survival (PFS) was 10 months. In pts with p53 defects (n = 8), ORR/CR were achieved in 5/2 pts (63/25%) with a median PFS of 10.5 months. The median overall survival (OS) was 34 months. The Grades 3–5 infectious toxicity in 33% of pts represented the most frequent side effect during the treatment period. In conclusion, the O‐Dex regimen shows a relatively high ORR and CR with promising findings for PFS and OS. The study was registered at www.clinicaltrials.gov (NCT01310101). Am. J. Hematol. 90:417–421, 2015. © 2015 Wiley Periodicals, Inc.     

Chemoimmunotherapy for relapsed/refractory and progressive 17p13‐deleted chronic lymphocytic leukemia (CLL) combining pentostatin,alemtuzumab, and low‐dose rituximab is effective and tolerable and limits loss of CD20 expression by circulating CLL cells

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients with purine analog refractory disease or TP53 dysfunction still have limited treatment options and poor survival. Alemtuzumab‐containing chemoimmunotherapy regimens can be effective but frequently cause serious infections. We report a Phase II trial testing the efficacy and tolerability of a short‐duration regimen combining pentostatin, alemtuzumab, and low‐dose high‐frequency rituximab designed to decrease the risk of treatment‐associated infections and to limit the loss of CD20 expression by CLL cells. The study enrolled 39 patients with progressive CLL that was either relapsed/refractory (n = 36) or previously untreated with 17p13 deletion (17p13?) (n = 3). Thirteen (33%) patients had both 17p13? and TP53 mutations predicted to be dysfunctional, and eight patients had purine analog refractory CLL without TP53 dysfunction. Twenty‐six (67%) patients completed therapy, with only five (13%) patients having treatment‐limiting toxicity and no treatment‐related deaths. Twenty‐two (56%) patients responded to treatment, with 11 (28%) complete responses (four with incomplete bone marrow recovery). Median progression‐free survival was 7.2 months, time to next treatment was 9.1 months, and overall survival was 34.1 months. The majority of deaths (82%) were caused by progressive disease, including transformed diffuse large B‐cell lymphoma (n = 6). Correlative studies showed that low‐dose rituximab activates complement and natural killer cells without a profound and sustained decrease in expression of CD20 by circulating CLL cells. We conclude that pentostatin, alemtuzumab, and low‐dose high‐frequency rituximab is a tolerable and effective therapy for CLL and that low‐dose rituximab therapy can activate innate immune cytotoxic mechanisms without substantially decreasing CD20 expression. Am. J. Hematol. 89:757–765, 2014. © 2014 Wiley Periodicals, Inc.     

Salvage outcomes in patients with first relapse after fludarabine,cyclophosphamide, and rituximab for chronic lymphocytic leukemia: The French intergroup experience

The optimal management of patients with relapsed chronic lymphocytic leukemia (CLL) is dictated by the type of prior therapy, duration of prior response, presence of genomic aberrations, age, and comorbidities. The patterns of relapses and the clinical outcomes of second‐line options after fludarabine‐cyclophosphamide‐rituximab (FCR) is given as a frontline treatment are currently unknown. In this retrospective and non‐randomized study, we report the outcomes of 132 patients from databases of 14 French CLL study group centers who needed a second‐line treatment after FCR frontline. Bendamustine + rituximab (BR) was the most frequently used second‐line regimen, followed by alemtuzumab‐based regimens, R‐CHOP, and FCR. Median progression‐free survival (PFS) was 18 months after BR with a median overall survival (OS) not reached. We also found that response durations of < 36 months and the presence of del(17p) are critical factors that contribute to poor overall survival. BR appears to be an effective salvage regimen in our series, both in terms of progression‐free and overall survival. Patients who relapsed less than 36 months after FCR have a poor outcome, not significantly different in this study from patients with early relapses less than 12 or 24 months. Am. J. Hematol. 90:511–514, 2015. © 2015 Wiley Periodicals, Inc.     

Outcome of allogeneic transplantation in newly diagnosed and relapsed/refractory multiple myeloma: long‐term follow‐up in a single institution

Allogeneic stem cell transplantation (allo‐SCT) has the potential to induce long‐term remission in multiple myeloma (MM), but the role of allo‐SCT in MM is controversial due to the high rate of treatment‐related mortality (TRM). However, although proteasome inhibitors and immunomodulatory drugs have improved the outcome of patients with MM, high‐risk patients still have a very poor prognosis. This indicates the need for new treatment strategies and identification of patients who might benefit from allo‐SCT. We therefore analyzed the outcome of one hundred and forty‐seven patients with MM who received an allo‐SCT at our institution (58 in first line, 89 in relapsed/refractory setting) after a median follow‐up of 88.8 months. For the first‐line setting, median progression‐free survival (PFS) and overall survival (OS) were remarkably good, with a CR rate of 48.3%, median PFS of 30.2 months, and 10‐yr OS of 51%. We found no difference in outcome for patients with high‐risk metaphase cytogenetics or FISH del(13q14), but efficacy in current standard high‐risk patients could not be determined. The outcome in the relapsed/refractory setting was poor, especially in the subgroup of patients relapsing within 18 months after auto‐SCT. Therefore, if applied at all in these patients, improvement of allo‐SCT is needed, focusing on reduction of TRM and more effective immunotherapy.     

Ublituximab (TG‐1101), a novel glycoengineered anti‐CD20 antibody,in combination with ibrutinib is safe and highly active in patients with relapsed and/or refractory chronic lymphocytic leukaemia: results of a phase 2 trial

Ibrutinib is effective in patients with chronic lymphocytic leukaemia (CLL); however, treatment resistance remains a problem. Ublituximab is a novel, glycoengineered anti‐CD20 monoclonal antibody with single‐agent activity in relapsed CLL. We report the results of a phase 2 study evaluating combination therapy with ibrutinib and ublituximab in patients with relapsed or refractory CLL. Patients received ibrutinib 420 mg once daily. Ublituximab was administered on days 1, 8 and 15 of cycle 1 followed by day 1 of cycles 2–6. Response assessments were completed at cycles 3 and 6; patients then continued on ibrutinib monotherapy per standard of care. Forty‐one of 45 enrolled patients were evaluable for efficacy. Safety was consistent with prior experience for each drug, with infusion reactions the most prevalent adverse event. Combination therapy resulted in an overall response rate (ORR) of 88% at 6 months. In the 20 patients with high‐risk features (17p or 11q deletions or TP53 mutation) and evaluable for efficacy, the ORR was 95%, with three patients (15%) achieving negative minimal residual disease. Median time to response was 8 weeks. Ublituximab in combination with ibrutinib resulted in rapid and high response rates. The long‐term clinical benefit of ublituximab will be defined by an ongoing phase 3 trial (NCT 02301156).     

A phase 2, randomized,double‐blind,placebo‐controlled study of siltuximab (anti‐IL‐6 mAb) and bortezomib versus bortezomib alone in patients with relapsed or refractory multiple myeloma

We compared the safety and efficacy of siltuximab (S), an anti‐interleukin‐6 chimeric monoclonal antibody, plus bortezomib (B) with placebo (plc) + B in patients with relapsed/refractory multiple myeloma in a randomized phase 2 study. Siltuximab was given by 6 mg/kg IV every 2 weeks. On progression, B was discontinued and high‐dose dexamethasone could be added to S/plc. Response and progression‐free survival (PFS) were analyzed pre‐dexamethasone by European Group for Blood and Marrow Transplantation (EBMT) criteria. For the 281 randomized patients, median PFS for S + B and plc + B was 8.0 and 7.6 months (HR 0.869, P = 0.345), overall response rate was 55 versus 47% (P = 0.213), complete response rate was 11 versus 7%, and median overall survival (OS) was 30.8 versus 36.8 months (HR 1.353, P = 0.103). Sustained suppression of C‐reactive protein, a marker reflective of inhibition of interleukin‐6 activity, was seen with S + B. Siltuximab did not affect B pharmacokinetics. Siltuximab/placebo discontinuation (75 versus 66%), grade ≥3 neutropenia (49 versus 29%), thrombocytopenia (48 versus 34%), and all‐grade infections (62 versus 49%) occurred more frequently with S + B. The addition of siltuximab to bortezomib did not appear to improve PFS or OS despite a numerical increase in response rate in patients with relapsed or refractory multiple myeloma. © 2014 Wiley Periodicals, Inc. Am. J. Hematol. 90:42–49, 2015. © 2014 Wiley Periodicals, Inc.     

Non‐myeloablative conditioning and allogeneic transplantation for multiple myeloma

In multiple myeloma (MM), allogeneic stem cell transplantation (alloHCT) carries a lower relapse risk than autologous transplantation but a greater transplant‐related mortality. Nonmyeloablative conditioning for allogeneic transplantation (NST) reduces transplant‐related toxicity. Results are encouraging when used during first remission in low‐risk patients, but less‐so in relapsed or refractory disease. This is a single‐center retrospective analysis of 20 previously treated MM patients who underwent NST from matched‐related or matched‐unrelated donors from 2000–2006. Median age was 52.7 years (37.2–68.0). Twenty‐five percent had advanced or high‐risk disease. Eleven still had active disease prior to NST. Conditioning was total body irradiation 200 cGy on a single fraction on day ?5, followed by antithymocyte globulin (ATG) 1.5 mg/kg/day and fludarabine 30 mg/m²/day on days ?4 to ?2. All received immunosuppression, most commonly with oral mycofenylate mofetil and cyclosporine beginning on day ?5. At day 100, 50% had achieved complete remission. Transplant‐related mortality was 25%. Median overall survival (OS) was 21.2 months (0.6–90+) and progression‐free survival (PFS) 6.6 months (0.6–90+). Both OS and PFS were 24% at 3 years. OS was significantly greater for patients with age <52 years (median 27 months vs. 7.9 months, P = 0.031), and there was a trend toward greater OS for those with β2 microglobulin <2.5 mg/l (median 27 months vs. 7.7 months, P = 0.08). Donor characteristics and Ig type had no significant effect on survival. These data suggest a benefit of NST in relapsed/refractory MM. Randomized trials must be performed to confirm and further qualify this benefit. Am. J. Hematol., 2010. © 2010 Wiley‐Liss, Inc.     

Outcomes with ibrutinib by line of therapy and post-ibrutinib discontinuation in patients with chronic lymphocytic leukemia: Phase 3 analysis

The efficacy of ibrutinib has been demonstrated in patients with chronic lymphocytic leukemia (CLL), including as first-line therapy. However, outcomes after ibrutinib discontinuation have previously been limited to higher-risk populations with relapsed/refractory (R/R) disease. The objective of this study was to evaluate outcomes of ibrutinib-treated patients based on prior lines of therapy, including after ibrutinib discontinuation. Data were analyzed from two multicenter phase 3 studies of single-agent ibrutinib: RESONATE (PCYC-1112) in patients with R/R CLL and RESONATE-2 (PCYC-1115) in patients with treatment-naive (TN) CLL without del(17p). This integrated analysis included 271 ibrutinib-treated non-del(17p) patients with CLL (136 TN and 135 R/R). Median progression-free survival (PFS) was not reached for subgroups with 0 and 1/2 prior therapies but was 40.6 months for patients with ≥3 therapies (median follow-up: TN, 36 months; R/R, 44 months). Median overall survival (OS) was not reached in any subgroup. Overall response rate (ORR) was 92% in TN and 92% in R/R, with depth of response increasing over time. Adverse events (AEs) and ibrutinib discontinuation due to AEs were similar between patient groups. Most patients (64%) remain on treatment. OS following discontinuation was 9.3 months in R/R patients (median follow-up 18 months, n = 51) and was not reached in TN patients (median follow-up 10 months, n = 30). In this integrated analysis, ibrutinib was associated with favorable PFS and OS, and high ORR regardless of prior therapies in patients with CLL. The best outcomes following ibrutinib discontinuation were for patients receiving ibrutinib in earlier lines of therapy.     

F‐18 FDG‐PET predicts outcomes for patients receiving total lymphoid irradiation and autologous blood stem‐cell transplantation for relapsed and refractory Hodgkin lymphoma

Total lymphoid irradiation (TLI) followed by high‐dose chemotherapy and autologous haematopoietic stem cell transplant (aHSCT) is an effective strategy for patients with relapsed/refractory classical Hodgkin lymphoma (HL). We report outcomes for patients with relapsed/refractory HL who received TLI followed by high‐dose chemotherapy and aHSCT. Pre‐transplant fludeoxyglucose positron emission tomography (FDG‐PET) studies were scored on the 5‐point Deauville scale. Of 51 patients treated with TLI and aHSCT, 59% had primary refractory disease and 63% had active disease at aHSCT. The 10‐year progression‐free survival (PFS) and overall survival (OS) for all patients was 56% and 54%, respectively. Patients with complete response (CR) by PET prior to aHSCT had a 5‐year PFS and OS of 85% and 100% compared to 52% and 48% for those without CR (P = 0·09 and P = 0·007, respectively). TLI and aHSCT yields excellent disease control and long‐term survival rates for patients with relapsed/refractory HL, including those with high‐risk disease features. Achievement of CR with salvage therapy is a powerful predictor of outcome.     

Autologous stem cell transplantation with in vivo purged progenitor cells shows long‐term efficacy in relapsed/refractory follicular lymphoma

High‐dose chemotherapy with autologous stem cell transplantation (ASCT) has been shown effective in the control of relapsed/refractory follicular lymphoma. We evaluate the long‐term outcome of patients with relapsed or refractory follicular lymphoma treated with ASCT with in vivo purged progenitors cells. We report the long‐term results of a prospective multicenter phase 2 trial on 124 relapsed/refractory follicular lymphoma patients treated with a program of anthracycline‐based debulking chemotherapy, immunochemotherapy, mobilization of in vivo purged PBSC followed by ASCT. Median age was 52 years; 14% of patients had grade 3A histology. Debulking chemotherapy produced CR in 16% and PR in 71%, while 13% of patients progressed. After rituximab, cyclophosphamide, vincristine, prednisone (R‐COP), CR was obtained in 60% and PR in 35%; 118 patients successfully mobilized PBSC and 117 proceeded to ASCT. The harvest in all the 32 molecularly informative patients was bcl‐2 negative. TRM was 0%. The 5‐year PFS was 54% and the 5‐year OS was 83%. After a median f‐up of 6.7 years (range 1.5–13.6), 54% are still in CR. These data show that prolonged PFS is achievable in relapsed/refractory patients with high dose autologous transplantation of in vivo purged progenitor cells. Am. J. Hematol. 90:230–234, 2015. © 2014 Wiley Periodicals, Inc.     

Outcomes in 370 patients with mantle cell lymphoma treated with ibrutinib: a pooled analysis from three open‐label studies

Ibrutinib is highly active in treating mantle cell lymphoma (MCL), an aggressive B‐cell lymphoma. We pooled data from three ibrutinib studies to explore the impact of baseline patient characteristics on treatment response. Patients with relapsed/refractory MCL (n = 370) treated with ibrutinib had an objective response rate (ORR) of 66% (20% complete response; 46% partial response); median duration of response (DOR), progression‐free survival (PFS) and overall survival (OS) were 18·6, 12·8 and 25·0 months, respectively. Univariate analyses showed patients with one versus >one prior line of therapy had longer OS. Multivariate analyses identified that one prior line of therapy affected PFS; Eastern Cooperative Oncology Group (ECOG) performance status, simplified MCL international prognostic index (sMIPI) score, bulky disease, and blastoid histology affected OS and PFS. Patients with blastoid versus non‐blastoid histology had similar time to best response, but lower ORR, DOR, PFS and OS. OS and PFS were longer in patients with better sMIPI, patients with ECOG performance status 0–1, non‐bulky disease and non‐blastoid histology. Additionally, the proportion of patients with poor prognostic factors increased with increasing lines of therapy. Together, results suggest that patient outcomes following treatment failure with ibrutinib are related to the natural biological evolution of the disease.     

Salvage therapy for acute myeloid leukemia with fludarabine,cytarabine, and idarubicin with or without gemtuzumab ozogamicin and with concurrent or sequential G‐CSF

The current salvage therapies for relapsed/refractory acute myeloid leukemia (AML) are unsatisfactory. Over the past 7 years, we have used two salvage regimens: fludarabine, cytarabine, and idarubicin with (FLAG‐IM) or without gemtuzumab ozogamicin (GO) (9 mg/m² on Day 8) (FLAG‐I) in relapsed/refractory AML. Three‐quarters of patients also received concurrent G‐CSF. Seventy‐one patients were treated, 23 with FLAG‐I and 48 with FLAG‐IM. The median duration of follow‐up was 30.6 months. The treatment groups were well balanced with median ages of 48 years (range 18–70) and 47 years (range 20–68), unfavorable cytogenetics in 57% and 35%, prior allogeneic stem cell transplant in 43% and 42%, and CR1 duration <1 year in 60% and 67%, respectively, for FLAG‐I and FLAG‐IM. The complete remission (CR) rate in the FLAG‐I group was 39% with an additional 13% achieving a CRp [overall response rate (ORR) 52%]; the CR rate in the FLAG‐IM group was 29% with an additional 27% achieving a CRp (ORR 56%). The median duration of response (DOR; 16.8 vs. 8.3 months), event‐free survival (EFS; 7.4 vs. 4.1 months), and overall survival (OS; 8.8 vs. 5.0 months) trended to favor FLAG‐I over FLAG‐IM. The patients who received G‐CSF concurrent with chemotherapy had superior overall response rate (ORR; 62% vs. 29%, P = 0.026), median EFS (6.2 vs. 3.4 months, P = 0.010), and OS (8.8 vs. 3.9 months, P = 0.004) when compared with those who sequentially received G‐CSF and chemotherapy, regardless of chemotherapy regimen. The addition of GO, at this dose and schedule, to FLAG‐I failed to improve the outcomes in patients with relapsed/refractory AML. The patients who received G‐CSF concurrently with chemotherapy had improved outcomes. Am. J. Hematol., 2009. © 2009 Wiley‐Liss, Inc.     

The combination of rituximab,bendamustine, and cytarabine for heavily pretreated relapsed/refractory cytogenetically high‐risk patients with chronic lymphocytic leukemia

Treatment of patients with B‐cell chronic lymphocytic leukemia (CLL) relapsed/refractory (R/R) to conventional treatments is particularly challenging. The combination of bendamustine and cytarabine has demonstrated distinct and synergistic mechanisms of action in preclinical studies on cell lines and primary tumor cells of several B‐cell lymphomas, including 17p deleted or TP53 mutated CLL. The efficacy of rituximab (375 mg/m², Day 1), plus bendamustine (70 mg/m², days 1–2), and cytarabine (800 mg/m², Day 1–3; R‐BAC), every 28 days for up to four courses, was evaluated in a pilot trial enrolling 13 patients with very selected high‐risk R/R CLL. All patients (median age 60 years, range 53–74) had symptomatic Binet stage B or C active disease requiring treatment, were characterized by adverse cytogenetics (17p deletion, 11q deletion, or both), unmutated immunoglobulin heavy‐chain variable region, and were heavily pretreated (1–5, median three previous lines). Overall, R‐BAC was well tolerated with limited non‐hematological toxicity. Major toxicities were transient Grade 3/4 neutropenia and thrombocytopenia in 84% and 85% of patients, respectively. Overall response rate (OR) was 84%, including complete and partial response in 38% and 46% of patients, respectively. Patients with 17p deletion had an OR of 78%. After a median follow‐up of 17 months, median progression‐free survival was 16 months while median overall survival (OS) was not reached (1‐year OS: 75 ± 13%). R‐BAC is an active regimen in R/R heavily pretreated high‐risk patients with CLL, representing an option for the treatment of patients that are usually refractory to standard therapy. Am. J. Hematol. 88:289–293, 2013. © 2013 Wiley Periodicals, Inc.     

A phase II study of two dose levels of ofatumumab induction followed by maintenance therapy in symptomatic,previously untreated chronic lymphocytic leukemia

Despite the recent advances in treatment of CLL with targeted agents such as ibrutinib, availability of nonchemotherapy based therapies is desired. Given the 58% response rate (1996 NCI‐WG criteria) of single agent ofatumumab in CLL refractory to fludarabine and alemtuzumab, we initiated a phase II trial examining response, safety, and progression‐free survival (PFS) of ofatumumab as front‐line monotherapy. Patients enrolled included untreated, symptomatic CLL patients over the age of 65 or those who were inappropriate/did not desire chemotherapy. Two cohorts were enrolled sequentially examining either 1 g (33 patients) or 2 g (44 patients) weekly for 8 weeks followed by maintenance dosing every 2 months for a total of 24 months. Patients receiving 1 g were older than those receiving 2 g, but there were no significant differences in other clinical characteristics. The best overall response rates in the 1 and 2 g patient cohorts were 72 and 89% (1996 NCI‐WG criteria), respectively (54 and 68%, respectively, using 2008 IWCLL criteria). All but two responses were partial. The 24‐month estimated PFS rates were 46 and 78%, respectively. Response and PFS was lower in del(17p) and del(11q) CLL patients. Differences in PFS between dose cohorts were statistically significant and remained so when adjusting for age or high‐risk cytogenetics. Toxicity of this treatment was mild with only six patients not completing therapy due to toxicity. Ofatumumab induction followed by maintenance therapy in untreated CLL represents a well‐tolerated and active regimen, particularly with the 2 g of ofatumumab. Am. J. Hematol. 91:1020–1025, 2016. © 2016 Wiley Periodicals, Inc.     

Long‐term analysis of phase II studies of single‐agent lenalidomide in relapsed/refractory mantle cell lymphoma

Mantle cell lymphoma (MCL) is a type of non‐Hodgkin lymphoma (NHL) with aggressive disease characteristics resulting in multiple relapses after initial treatment. Lenalidomide is an immunomodulatory agent approved in the US for patients with relapsed/refractory MCL following bortezomib based on results from 3 multicenter phase II studies (2 including relapsed/refractory aggressive NHL and 1 focusing on MCL post‐bortezomib). The purpose of this report is to provide longer follow‐up on the MCL‐001 study (follow‐ups were 6.8 [NHL‐002], 7.6 [NHL‐003], and 52.2 [MCL‐001] months). The 206 relapsed MCL patients treated with single‐agent lenalidomide (25 mg/day PO, days 1 to 21 every 28‐days) had a median age of 67 years (63% ≥65 years), 91% with stage III/IV disease, and 50% with ≥4 previous treatment regimens. With a median follow‐up of X, the combined best overall response rate (ORR) was 33% (including 11% with complete remission [CR]/CR unconfirmed CRu). Lenalidomide produced rapid and durable responses with a median time to response of 2.2 months and median duration of response (DOR) of 16.6 months (95% CI: 11.1%‐29.8%). The safety profile was consistent and manageable; myelosuppression was the most common adverse event (AE). Overall, single‐agent lenalidomide showed consistent efficacy and safety in multiple phase II studies of heavily pretreated patients with relapsed/refractory MCL, including those previously treated with bortezomib.