Case study 32.1
A 56-year-old male presented for his annual physical examination. Over the past year, he has done well but had noted slight fatigue, which he attributed to increased stress at work; he was otherwise asymptomatic. A complete blood count (CBC) demonstrated a white blood cell (WBC) count of 33,000 with 87% mature-appearing lymphocytes on peripheral smear, a hemoglobin (Hb) level of 13.7 g/dL, and a platelet count of 278,000. On physical examination he was noted to have mild (1–2 cm) cervical and axillary adenopathy; the spleen tip and liver edge were not palpable. A peripheral blood sample was sent for flow cytometric analysis and demonstrated a monoclonal B-lymphocyte population expressing CD5, CD19, CD20, CD22(dim), CD23, CD79(dim), and SmIg(dim); they were negative for CD38 and FMC7. A bone marrow examination demonstrated 40% lymphocytes with a diffuse histopathologic pattern. Cytogenetic analysis revealed a normal 46XY karyotype; however, fluorescence in situ hybridization (FISH) studies demonstrated an 11q deletion in 79% of cells. IgVH (immunoglobulin heavy-chain variable-region) mutational status was not performed. The patient was diagnosed as having B-cell chronic lymphocytic leukemia (CLL) and staged as Rai stage 0. It was recommended that the patient be closely observed with follow-up every 3 months. At a follow-up visit 6 months later, the patient complained of increased fatigue and occasional night sweats. On physical examination, his adenopathy had increased in both size and extent. A CBC demonstrated a WBC of 78,000 with 92% mature-appearing lymphocytes on peripheral smear, an Hb of 12.3 g/dL, and a platelet count of 213,000. A decision was made to begin treatment with the FCR regimen (fludarabine, cyclophosphamide, and rituximab) of which he received six cycles. At the completion of therapy, his adenopathy had almost completely resolved, and a CBC demonstrated a WBC of 6700 with 13% lymphocytes on peripheral smear, an Hb level of 14.3 g/dL, and a platelet count of 303,000. The decision was made to closely observe. The patient did well for approximately 11 months, at which time he called the office to say that he could palpate his cervical lymph nodes. He was found to have significant cervical adenopathy (3–4 cm) as well as diffuse adenopathy documented by a computed tomography (CT) scan. A CBC demonstrated a WBC of 59,000 with 89% mature-appearing lymphocytes on peripheral smear. The patient was treated with bendamustine plus rituximab for four cycles, resulting in a complete response. On follow-up 15 months later, a CBC demonstrated evidence of recurrent disease with a WBC of 29,000 with 72% mature-appearing lymphocytes on peripheral smear. He was also found to have a new left inguinal lymph node. An excisional lymph node biopsy demonstrated small lymphocytic lymphoma and no evidence of Richter’s transformation. The patient was referred to a tertiary center for treatment options, including hematopoietic stem cell transplantation (HSCT). The patient has three living siblings who are in good health. A decision is made to treat the patient with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).
• Is it appropriate to consider HSCT for the patient at this time?
The patient has been treated with a fludarabine-based regimen and second-line treatment with a bendamustine-based regimen. He is relatively young and has high-risk features, with an 11q deletion and relatively short response durations to his two lines of treatment. Taken together, it is appropriate to consider transplantation as a treatment option. Whether the patient is an appropriate transplantation candidate is dependent on a number of factors, including the patient’s response to third-line therapy, the availability of a donor, and ultimately whether the patient is willing to accept the toxicities associated with HSCT.
• If the patient does not have a responsive disease, is transplantation contraindicated?
Chemotherapy sensitivity is known to be an important prognostic factor; however, there are patients who lack chemotherapy sensitivity, generally defined as at least a partial response (PR), who can achieve long-term remissions and survival with allogeneic HSCT. Pavletic and collaborators (2000) at the University of Nebraska and Vanderbilt University reported on the results of 23 CLL patients who underwent myeloablative allogeneic HSCT, including 14 patients with chemotherapy-refractory disease, 12 of which were refractory to fludarabine. At the time of this report, 14 (61%) patients were alive and disease free, including eight patients with chemotherapy-refractory disease at a median follow-up of 26 months (range: 9–115 months). In univariate analysis, chemotherapy sensitivity was not significant (P = 0.853) relative to overall survival.
The Chronic Leukemia Working Party of the European Blood and Marrow Transplantation Group (EBMT) reported on the results of 77 CLL patients from 29 EBMT centers who underwent allogeneic HSCT using reduced-intensity conditioning. In a multivariate analysis, they observed that patients who had less than PR at the time of transplantation were at increased risk for relapse (hazard ratio = 3.5 (1.4–8.70; P < 0.01); however, it was a nonsignificant factor relative to overall survival. Similarly, Khouri and colleagues at the MD Anderson Cancer Center (2011) reviewed the results of 86 patients with relapsed and refractory CLL who were enrolled on sequential nonmyeloablative allogeneic HSCT protocols at their institution. In multivariate analysis, disease status at transplantation did not have a significant impact upon outcome, which may have been affected by the use of posttransplant immunomodulation in their treatment strategy.
In summary, lack of chemotherapy sensitivity is not an absolute contraindication to allogeneic HSCT. It does appear that results are improved, particularly in regard to progression-free survival (PFS), in patients who have chemotherapy-sensitive disease, and it is desirable to enter into transplant with as low a disease burden as possible. In my own practice, I have found that patients with truly progressive disease at the time of transplant rarely, if ever, benefit from HSCT, and I advise against transplantation for these patients. However, I will offer patients with stable disease the option of allogeneic HSCT, explaining that the risk of relapse is increased.
• What if the patient does not have a human leukocyte antigen (HLA)-matched sibling? Are the results significantly worse with a well-matched volunteer unrelated donor?
Similar to results in the acute leukemias, there are reports that outcomes are worse with unrelated donors. However, subsequent studies have demonstrated that outcomes are equivalent and possibly even superior with unrelated donors. The Cooperative German Transplant Study Group reported on 30 patients with advanced B-cell CLL who underwent reduced-intensity allogeneic HSCT. Fifteen patients received cells from HLA-related donors, and the other 15 from HLA-matched unrelated donors. After a median follow-up of 2 years, the probability of overall survival and PFS at 2 years for all patients was 72% and 67%, respectively. Acknowledging that the numbers were small, there was no difference in PFS between recipients of related and unrelated donors (70% vs. 67%; P = 0.6735).
The Seattle transplantation group performed an outcomes analysis on 64 patients with advanced CLL treated with nonmyeloablative allogeneic HCST; 44 were from related donors, and 20 were from unrelated donors. The 2-year rates of overall and disease-free survival were 60% and 52%, respectively. Recipients of unrelated donors were observed to achieve higher complete remission and lower relapse rates than recipients of related donors, suggesting more effective graft-versus-leukemia activity. These data are intriguing and suggest that although they may result in higher treatment-related morbidity and mortality, the use of unrelated donors can result in similar outcomes as measured by PFS and overall survival.
• Is there a stage of disease at which HSCT is no longer of any benefit?
This is an essential question and can be looked at from several perspectives. “Stage of disease,” as defined by chemotherapy sensitivity, was addressed above. From another perspective, it comes down to an issue of timing. Again, using the acute leukemias (and, to a similar degree, our previous experience with chronic myeloid leukemia), it has been observed that the earlier in the patient’s disease course that transplantation is utilized, the better the outcomes. There is some evidence to support similar observations in patients with CLL who have undergone allogeneic HSCT, yet there are data that contradict this assumption. In their admittedly small patient population (n = 30), the Cooperative German Transplant Study Group did not observe any difference in PFS among patients who had three or fewer prior therapies as compared to patients who had received more than three prior chemotherapy regimens (75% vs. 56%; P = 0.4454).
Similar results were reported from the German CLL Study Group CLL3X trial. This prospective, multicenter phase II trial was designed to investigate the long-term outcome of reduced-intensity conditioning allogeneic HSCT in patients with poor-risk CLL. One hundred eligible patients were enrolled, and 90 patients proceeded to allogeneic HSCT. At a median follow-up of 46 months (range: 7–102 months), the 4-year event-free survival and overall survival rates were 42% and 65%, respectively. In univariate analysis, neither the time interval from diagnosis to allogeneic HSCT (≥5 years vs. <5 years; P = 0.14) nor the number of previous regimens (≥3 vs. <3; P = 0.85) was found to correlate with overall survival. It is of note that in this trial, chemotherapy-refractory disease did adversely correlate with overall survival (P = 0.023) in multivariate analysis. Based on these data, it does not appear that the use of allogeneic HSCT later in the disease course of CLL patients significantly affects outcomes.
• What is the quality of life like for CLL patients who undergo allogeneic HSCT?
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17: Management of Therapy-Related Myeloid Neoplasms
11: Minimal Residual Disease in Acute Myeloid Leukemia
71: Secondary Brain and Spinal Cord Tumors
