Mini Review Should HIV-Positive Patients with Lymphoma Be Offered Stem Cell Transplants?

Mini review Should HIV-positive patients with lymphoma be offered stem cell transplants?

A Krishnan, J Zaia and SJ Forman

Hematologic Neoplasia Program, City of Hope Comprehensive Cancer Center, Duarte, CA, USA

Summary: Moreover, recently we have come to recognize that Hodgkin’s (HD) lymphoma is also increased in incidence Advances in effective antiretroviral therapy for HIV in HIV-infected patients.3 When these lymphomas occur in infection have made high-dose therapy and autologous association with HIV infection, they tend to present with an stem cell transplantation possible in patients with HIV- advanced stage, B symptoms, extranodal sites of disease associated lymphomas. Regimen-related toxicity is not and commonly bone marrow involvement.4–6 Prognostic significantly increased when antiretroviral therapy is factors associated with shortened survival for HIV-asso- combined with high-dose chemoradiotherapy. Durable ciated NHL include age 435 years, a history of intra- engraftment can be seen with autologous stem cell rescue. venous drug abuse, stage III or IV disease, CD4 counts Infectious complications can be managed with a combina- o100 and an elevated LDH.7 In addition, the international tion of surveillance and prophylaxis. Long-term remis- prognostic index has been found to be highly correlated sions of these high-risk lymphomas can be achieved with with survival.8 this approach. This suggests that patients with HIV- Historically, prior to effective antiretroviral therapy, the associated lymphomas should be considered for autolo- treatment of both HIV-NHL and HD was hampered by gous transplantation in a manner similar to HIV-negative high rates of opportunistic infections (OIs) and cytopenias lymphoma patients from the underlying HIV infection. This led to the early Bone Marrow Transplantation (2003) 32, 741–748. treatment paradigm that less intensive chemotherapy was doi:10.1038/sj.bmt.1704270 sufficientand less toxic. 9 However, the results with either Keywords: HIV lymphoma; autologous stem cell trans- conventional or dose-reduced treatment were poor and far plantation worse than in the HIV-negative lymphoma setting.9,10 For example, in the AIDS Clinical Trial Group study of low- dose M-BACOD (methotrexate, bleomycin, doxorubicin, The advent of highly active antiretroviral therapy cyclophosphamide, vincristine, dexamethasone) vs conven- (HAART) has led to new treatment options for patients tional dose M-BACOD, the median survival was only 35 with HIV and other concurrent medical conditions either and 31 weeks, respectively. Similarly for HIV-HD, a trial related or unrelated to their HIV infection. For example, using standard-dose ABVD (adriamycin, bleomycin, vin- centers in several states are now performing solid organ blastine, dacarbazine) with growth factor support resulted transplants in HIV-positive individuals with life-threaten- in neutropenia in approximately 50% of the patients with a 11 ing end-stage organ disease who fulfill the other requisite median survival of only 18 months. Treatment options for criteria for renal or liver transplantation.1 This brings to the relapsed HIV-related HD or NHL are even more limited, forefront the question for bone marrow transplant centers: with the majority of studies reporting median survivals of 12,13 should we routinely consider high-dose chemotherapy only 3–7 months. Thus, new treatment strategies such (HDC) with autologous stem cell transplantation (ASCT) as ASCT are worthy of further study in these high-risk for patients with HIV infection and lymphoma? lymphomas.

Effects of HAART Clinical features of HIV-associated lymphomas Does HAART lower the incidence of HIV lymphoma? It has long been recognized that the incidence of non- Hodgkin’s lymphoma (NHL) is increased in HIV-infected HAART changed the course of HIV infection by increasing individuals and is considered an AIDS-deﬁning illness.2 CD4 counts, reducing the incidence of OIs and ultimately prolonging survival (Table 1).14 Itis also clear that HAART has reduced the incidence of Kaposi’s sarcoma 15 Correspondence: Dr A Krishnan, Hematologic Neoplasia Program, City and primary CNS lymphoma. The effects on other of Hope Comprehensive Cancer Center, 1500 East Duarte Road, lymphomas are less clear. A large multicenter European Duarte, CA 91010, USA. E-mail: [email protected] study showed a decrease in the proportion of new AIDS Stem cell transplants for HIV-positive lymphoma patients A Krishnan et al 742 Table 1 Effects of HAART on NHL CR rates are impressive at 79%, with no CR patient thus far having relapsed.23 Decreased incidence of Kaposi’s sarcoma May decrease the incidence of NHL Thus, most studies suggest that HAART can be Increased CD4 counts combined with chemotherapy in various ways. The use of Decreased incidence of opportunistic infections concomitant therapies may improve CR rates and lead to Increased hematologic reserve improved survival. Attention should be paid to increased Increased neurotoxicity with concomitant chemotherapy Increased mucositis with concomitant chemotherapy neurotoxicity. In addition, it is prudent to avoid HAART May increase CR rates with chemotherapy regimens containing potentially highly myelosuppressive Allows mobilization of stem cells agents such as zidovudine (AZT) and others, such as lamivudine, which are potentially myelosuppressive.

cases due to OIs in the era of HAART, but an increase in the proportion of new AIDS secondary to lymphoma.16 In HDC and HAART contrast, an international collaborative study combining data from over 20 trials did show a reduction in the Randomized trials have demonstrated that HDC with lymphoma incidence from the pre HAART era (1992–1996) ASCT improves overall survival over conventional dose vs 1997–1999. Of note, the incidence of immunoblastic and salvage therapy for patients with relapsed NHL.24,25 primary CNS lymphoma declined mostsignificantly,while Similarly, for patients with relapsed HD, this approach there was no decline in the incidence of Burkitt’s lymphoma has demonstrated improved disease-free survival.26 As the or HD.17 upfront mortality of ASCT has significantly decreased, centers worldwide have conducted studies in HIV-negative 26,27 Can we combine HAART with chemotherapy? patients with high-risk first-remission disease. Given the high-risk features of HIV-associated lymphomas, as well as The improvement in immune function and hematologic the lack of effective salvage regimens for relapsed disease, reserve with HAART has led to interest in its use in transplant centers such as the City of Hope Comprehensive combination with antilymphoma chemotherapy. An AIDS Cancer Center have explored the use of dose-intensive malignancy consortium study combined a HAART regi- chemotherapy and ASCT in conjunction with HAART. men of stavudine, lamivudine and indinavir with either standard- or reduced-dose CHOP (cyclophosphamide, Can HIV lymphoma patients mobilize stem cells? adriamycin, vincristine, prednisone). Cyclophosphamide clearance was reduced in patients on concomitant HAART The ability to mobilize stem cells was the first theoretical when compared to historical controls. However, no clinical hurdle to ASCT in HIV-positive patients. The presence of consequences from this were apparent.18 Other studies have multilineage cytopenias in HIV-infected individuals sug- suggested an increase in neurotoxicity when CHOP is gests that the effects of the virus on marrow suppression are combined with HAART (13% in the HAART group vs 0% more far reaching than on the T-cell subsets only. in the no-HAART group), but this has not been dose Alterations in the bone marrow microenvironment and limiting.19 One study also raises the concern of increased the cytokine milieu are some of the postulated mechan- mucositis when combining infusional chemotherapy CDE isms.28,29 Of note, several experimental models have (cyclophosphamide, doxorubicin, etoposide) with nucleo- demonstrated that primitive hematopoietic progenitor cells side analogues.20 Furthermore, a recent study evaluating are not directly infected by the virus, although their immune parameters of patients on concomitant HAART functioning can be disturbed by the presence of the virus.29 and chemotherapy demonstrated that patients can main- HAART has favorable effects on the hematologic reserves, tain an undetectable viral load and recover CD4 counts to as demonstrated by increases in white blood cell and baseline after completion of chemotherapy.21 Similarly in platelet counts as viral loads decline.30 Therefore, with the HIV-HD, the combination of conventional chemotherapy advent of effective antiretroviral regimens, stem cell regimens with HAART has been well tolerated and may mobilization in HIV-infected patients became possible. even lead to improved survival. For example, an Italian Furthermore, studies from our institution found no long- study combined the multidrug Stanford V regimen with term deleterious effects of the GCSF used for mobilization HAART, and a complete remission rate of 81% was on the HIV viral load, and in addition demonstrated the achieved with an estimated 3-year survival of 51%.22 potential of these apheresed stem cells to differentiate and An alternate approach has been taken by investigators at produce normal numbers of hematopoietic cells.31 In the NCI in which HAART was temporarily suspended patients with HIV and lymphoma, we used the last cycle during the time of chemotherapy. They utilized infusional of lymphoma chemotherapy as the mobilizing regimen EPOCH (etoposide, vincristine, cyclophosphamide, doxor- followed by GCSF (10 mg/kg/day). We discontinued ubicin, prednisone) with growth factor support. All trimethoprim–sulfamethoxasole (TMP–SMX) during this antiretroviral therapy was held until day 6 of the last dose period to avoid possible myelosuppression. A total of 19 of chemotherapy. Despite an increase in HIV viral loads up patients have undergone apheresis with a median of to 1000-fold by cycle 4 of therapy, within 3 months of 10.5 Â 106 CD34 þ cells/kg collected. The reason for this restarting HAART, the viral load returned to pretreatment relatively high number is that five patients had additional levels. CD4 counts recovered by 12–24 months post stem cells collected as part of a gene therapy trial. We treatment, and no increase in OIs was seen. The initial process the cells in the same manner as HIV-negative

Bone Marrow Transplantation Stem cell transplants for HIV-positive lymphoma patients A Krishnan et al 743 products using ‘universal precautions’. The products are based regimen of total body irradiation (TBI) 1200 cGy, stored in a separate designated freezer and labeled as an cyclophosphamide 100 mg/kg, etoposide 60 mg/kg in three. HIV-positive unit. Patients were maintained on HAART throughout the In this series, 16 patients were on a non-AZT HAART transplant if possible, although 10 were intolerant due to regimen and mobilized stem cells in a time course similar gastrointestinal toxicity, such as either nausea, vomiting or to our HIV-negative lymphoma patients. Three recent mucositis. All patients did develop hepatotoxicity, although patients were on an AZT combination regimen as part of in the majority it was grade 1–2. Three patients developed Trizivir or Combivir (Table 2) and one experienced grade 3–4 hepatotoxicity – two due to the conditioning significant difficulty with mobilization requiring 10 days regimen, one ultimately died of multiorgan failure at day of apheresis and one had delayed engraftment. We, þ 22 post transplant. The third patient had late hepatotoxi- therefore now recommend that all patients be switched city at 10 months post ASCT that was ultimately ascribed to from AZT to an alternate antiretroviral medication during his antiretroviral regimen as it resolved when these medica- chemotherapy and apheresis. tions were discontinued. No patient developed neurotoxicity. Severe mucositis was seen in the patients receiving TBI, which is an expected complication of this regimen. Is there increased toxicity when we combine HAART and Similarly, investigators from France have reported their HDC? ASCT experience in 14 patients with HIV lymphoma As we previously mentioned, there has been great concern (Table 3). Eightreceived an FTBI-based regimen and six about increased organ toxicity due to the protease received a chemotherapy-based regimen. Regimen-related inhibitors inhibiting specific cytochrome P-450 enzymes toxicities were not reported to be increased over the HIV- that are important for chemotherapy metabolism. In a case negative setting.33 Other centers have transplanted smaller report of solid organ transplantation in a patient with HIV, numbers of patients with a variety of conditioning regimens the patient developed seizures from supratherapeutic levels including nonmyeloablative regimens.34–36 The overall of immunosuppressive medications in part due to impaired trend is similar in that engraftment was achieved and only metabolism of these medications due to his HIV anti- transient increases in HIV viral load were observed retroviral regimen.32 The increased neurotoxicity and (Table 3).34–36 hepatotoxicity seen with concomitant HAART and con- In the 19 patients from the City of Hope series, the ventional dose chemotherapy may be of further concern in median time to neutrophil engraftment was 11 days (range the high-dose setting.19,20 9–23), a time course similar to the HIV-negative patients. We have transplanted a total of 19 HIV lymphoma However, one of the recent patients in our series (UPN416) patients (see Table 2) with either a chemotherapy-based was maintained on his AZT combination regimen during the regimen of CBV (cyclophosphamide 100 mg/kg, carmustine transplant. It is our impression that this led to the marked 450 mg/m2, etoposide 60 mg/kg) in 16 or a radiotherapy- delays in his engraftment. White cell engraftment was at 23

Table 2 Demographics and status of 19 HIV lymphoma patients undergoing ASCT

UPN Diagnosis Disease status HAART Prior chemotherapy Status

202 NHL 1stREL Nf, L, S CHOP CR; 44 mo 203 HD 1stREL I, L, S CHOP, Ifos/VP16, ESHAP CR; 38 mo 204 NHL 1stPR Nf, L, S CHOP, ESHAP Relapse/death4 mo 208 NHL 1stCR Nf, Nv, S CHOP, ESHAP CR; 32 mo 209 HD 1stREL I, L BOSE, ABVD, ESHAP CR; 33 mo 400 NHL 2nd CR Nf, Nv, L POG-8617, -9517, and –9317 Relapse/death 4 mo 405 NHL 1stPR I, L, S CHOP, ESHAP, RTX CR; 43 mo 406 NHL 1stCR R, S, Nv, Sa CHOP CR; 55 mo 407 NHL 3rd CR E, L, S CHOP, Ifos/VP16, RTX, ESHAP CR; 37 mo 408 NHL 1stCR R, S, Sa CHOP CR; 24 mo 409 NHL 1stPR L, A, Nf CHOP, ESHAP Deathday 22 410 NHL 1stPR L, E, Sa M-BACOD, RTX, ESHAP CR; 26 mo 411 NHL 1stREL S, E, Nf CHOP, ESHAP/RTX CR; 27 mo 412 NHL 1stPR S, E, L CAV, Ara C/MTX, CODOX-M CR; 17 mo 413 NHL 1stREL L, E, S CHOP, ESHAP, RTX CR; 20 mo 414 NHL 2nd REL E, TR EPOCH, RTX, ESHAP, Cy/Tax CR; 8 mo 415 NHL 1stREL ABC, R, E CHOP, RTX, ESHAP CR; 11 mo 416 NHL 2nd REL CO, NV CHOP, ESHAP, RTX CR; 9 mo 417 NHL 1stCR ABC, E, CO EPOCH, CHOP CR; 9 mo

ABC ¼ abacavir; ABVD ¼ adriamycin, bleomycin, vincristine/vinblastine, dacarbazine; Ara C/Mtx ¼ cytarabine, methotrexate; BOSE ¼ bleomycin, oncovin, streptozocin, etoposide; CAV ¼ cyclophosphamide 400 mg, vincristine 2 mg, adriamycin 40–60 mg; CHOP ¼ cyclophosphamide, adriamycin, vincristine, prednisone; CO ¼ combivir; CODOX-M ¼ cyclophosphamide, vincristine, adriamycin, methotrexate; CR ¼ complete response (remission); E ¼ efavirenz; ESHAP ¼ etoposide, cytarabine, cisplatinum, prednisone; I ¼ indinavir; Ifos/VP16 ¼ ifosfamide/etoposide; L ¼ lamivudine; M-BA- COD ¼ methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, cytarabine, dexamethasone; Nf ¼ nelﬁnavir; Nv ¼ nevirapine; POG8617 ¼ cyclophosphamide, adriamycin, cytarabine; POG9317 ¼ Ifos, VP16, methotrexate, cytarabine; POG9517 ¼ same plus methotrexate, Ifos, VP16; R ¼ ritonavir; RTX ¼ rituxan; Sa ¼ saquinavir; S ¼ stavudine, TR ¼ trizivir, mo ¼ months.

Bone Marrow Transplantation oeMro Transplantation Marrow Bone 744 tmcl rnpat o I-oiielmhm patients lymphoma HIV-positive for transplants cell Stem Table 3 Transplantation in HIV lymphoma

Histol DZ status No.on HAART Conditioning regimen Viral load post ASCT OI Engraftment WBC Outcome

Gabarre et al 33 6 HD, 3BL, 2IL, Nine 1stREL 8, one 13 (details N/A) 6 HDC, 8 2 transient rise 2 CMV viremia N/A 6 alive (1 CR 1 PEL, 2 DLCL 2nd REL, one 3rd HDC+TBI (1–31 mo)), 6 died REL, one 4th from NHL/HD REL, two (2–6 mo), 1 died primary from AIDS refractory (no HAART), 1 died from 2nd malignancy Krishnan A

Serrano et al 35 1 HD, 2 BL, 2 Four 1stCR, four 5a 5 BCNU/ No change N/A 14–21 days 5 alive CR NHL 2nd CR etoposide, (2–14 mo) cytarabine/ al et melphalan

Campbell et al 36 1 DLCL 1stREL 1 Cyclophosphamide/ No change None 9 days 1 alive (syngeneic) BCNU, etoposide CR (12 mo)

Kang et al 34 1 HD (1 AML) Primary 1 Cyclophosphamide Temporary rise to 1 Toxoplasmosis, Notapplicable – 1 died 12 mo from (allogeneic) refractory ﬂudarabine 106 copies/ml 2 CMV viremia nonmyeloablative HD HD

Krishnan et al 38 2 HD, 17 NHL Four 1stCR, six See Table 1 16 cyclophosphamide/ Transientrise 2 PCP pneumonia, 9–23 days 16 alive 1stREL, ﬁve 1st BCNU/etoposide 2 CMV viremia, (6–57 mo), 2 died PR, one 2nd CR, 3 cyclophosphamide/ 1 CMV retinitis, from NHL (4 mo), two 2nd REL, etoposide/TBI 1 zoster 1 died from one 3rd CR regimen toxicity

BL ¼ Burkitt’s lymphoma; DLCL ¼ diffuse large-cell lymphoma; IL ¼ Immunoblastic lymphoma; HD ¼ Hodgkin’s disease; HDC ¼ high-dose chemotherapy; N/A ¼ notavailable; PEL ¼ primary effusion lymphoma; TBI ¼ total body irradiation; mo ¼ months. aOne patient had HAART held during conditioning. Stem cell transplants for HIV-positive lymphoma patients A Krishnan et al 745 days and platelets at 156 days post ASCT. Hence, our Table 4 Practice points to remember current treatment strategy is either to hold HAART until Time period To do engraftment if no AZT substitute can be used, or if possible to change to an alternate antiretroviral regimen. In contrast, Pre transplant Assess viral load (o10 000 copies/ml preferred) Serrano et al 35 found delayed engraftment in both platelets screening and neutrophils in the HIV-positive lymphoma patients Lumbar puncture with cytology Bone marrow for MAI when compared to an HIV-negative cohort. However, No recent opportunistic infection details of the HAART regimen used are not provided. Apheresis Non-AZT HAART regimen Change TMP–SMX to alternate PCP regimen Can we perform ASCT without increasing AIDS-related (pentamidine or dapsone) complications? ASCT Continue HAART but watch for drug interactions Another initial barrier to transplantation in HIV-infected Antifungal prophylaxis – amphotericin or fluconazole patients was the concern that the increased immunosup- PCP prophylaxis with pentamidine till engraftment, pression from the transplant may ultimately lead to early then TMP–SMX Antimicrobial prophylaxis with levofloxacin mortality from OIs. Certainly, the early transplant experi- Monitor for hepatoxicity ence prior to HAART demonstrated exactly that problem.37 However, with current treatment options and appropriate PostASCT PCP prophylaxis – TMP–SMX preferred if stable prophylaxis againstOI, no patientinour series died of an graft Start MAI prophylaxis (azithromycin) infectious complication. In our protocol, patients are Start herpes zoster prophylaxis (acyclovir) maintained on pentamidine for pneumocystis (PCP) Biweekly monitoring for CMV till day +100 prophylaxis during apheresis. During the transplant, Continue or resume HAART levofloxacin is started at day À9 for gut decontamination Start or continue antifungal prophylaxis, fluconazole and TMP–SMX is also used from days À9toÀ2 for PCP preferred if LFT is stable prophylaxis. Intravenous acyclovir is used for herpes ASCT ¼ autologous stem cell transplant; MAI ¼ Mycobacterium avium prophylaxis and either low-dose amphotericin (0.15 mg/ intracellulare; PCP ¼ Pneumocystis pneumonia; TMP–SMX ¼ trimethro- kg) or fluconazole 200 mg/day is used for antifungal trimethroprim–sulfamethoxasole. prophylaxis. After engraftment, we continue TMP–SMX and also use high-dose oral acyclovir for zoster prophylaxis for 1-year post ASCT. In addition, azithromycin is used for transplant series of two patients, both developed CMV Mycobacterium avium complex prophylaxis until CD4 viremia and one developed central nervous system toxo- counts have reached stable levels. Lastly, surveillance plasmosis.34 Hence, our feeling is that infectious complica- cultures for cytomegalovirus are performed weekly until tions are a concern but can be minimized with an day 100 (see Table 4). þ appropriate strategy of close surveillance and prophylaxis. With this strategy, infectious complications pre engraftment were similar to HIV-negative patients, with Gram-positive bacteremias predominating. Two patients What happens to the HIV infection during and developed a fulminant engraftment syndrome-type picture after the transplant? with high fevers and skin rashes and negative blood cultures. This responded to steroids. Post engraftment, Another concern with an autologous transplant strategy the most serious infections were respiratory with four was recovery of CD4 counts and effects on the HIV viral patients developing bacterial pneumonias. In the patients load. Specifically, are we curing the lymphoma but at the with frequent respiratory infections, we now also check price of worsening the HIV infection? immunoglobulin levels for the first year post transplant and In an attempt to optimize control of the HIV infection, give replacementtherapyas needed. we attempted to continue HAART during the transplant. Five patients did develop OIs. Two patients developed The hope was that control of viral replication would allow PCP pneumonia. Although of note, both these patients were engraftment and minimize infectious risks. We initially had not compliant with prophylaxis. One of these patients also no restrictions on the type of antiretroviral regimen used. developed CMV retinitis and the other soon after his PCP However, after the prolonged engraftment seen in patients pneumonia developed Aspergillus pneumonia.Thiswas on zidovudine, we now prohibit its use either as a single presumed to be from the steroids required for his PCP agentor as a combinationpill (Trizivir, Combivir). A large pneumonia therapy. He is currently on outpatient antifungal portion of our patients and those in the French series were therapy and appears to be responding. One patient on stavudine, a nucleoside analogue, which is generally well developed disseminated herpes zoster, which was prior to tolerated except for mild nausea. Its absorption is not our routine use of acyclovir prophylaxis post ASCT. One affected by meals and it has no significant drug interac- patient developed CMV viremia and low-grade fevers at day tions. These patients were also often taking the nucleoside þ 37 that responded to therapy and one patient developed analogue lamivudine, which similarly has no reported drug asymptomatic CMV viremia that did not require treatment. interactions and is rapidly absorbed after oral administra- Similarly, in the French series, two patients developed CMV tion. In terms of protease inhibitors, patients were taking viremia postASCT notassociated withorgan-specific either saquinavir, indinavir or ritonavir. Saquinavir has disease33 (Table 3). Also of note, in the nonmyeloablative limited bioavailability. The major concern in the setting of

Bone Marrow Transplantation Stem cell transplants for HIV-positive lymphoma patients A Krishnan et al 746 the transplant is that it is metabolized by the cytochrome antiretroviral therapy in order to optimize outcome from P-450 system. Therefore P-450, 3A4 inhibitors may raise the transplant. levels of saquinavir. In contrast, saquinavir inhibits P-450CYP3A and therefore, it may elevate plasma Can we cure HIV lymphoma with ASCT? concentrations of drugs metabolized by this enzyme such as midazolam and triazolam. Similarly, the other protease In our series of 19 patients, three have died: two from inhibitors indinavir and ritonavir have inhibitory effects on relapsed lymphoma early postASCT and one from regimen the P-450CYP3A system and therefore, comparable drug related toxicity. In all, 16 patients are alive and in remission interactions to saquinavir. Despite the attempt to continue with a median follow-up of 27.5 months (6–57.5 months) HAART, in fact, the majority of patients were unable to (Figure 2). tolerate it during the transplant due to either nausea or In the French cohort, six patients died from relapsed mucositis. If patients miss doses due to nausea, we do not lymphoma, one from AIDS and one from a second advocate redosing. If patients missed many doses, we malignancy. Details of the extent of prior therapy of these subsequently discontinued therapy until recovery from the patients were not published; however, one can postulate transplant rather than continuing an intermittent erratic that the more favorable results from our series may in part dosing schedule. be due to the earlier use of transplantation. Many of the As expected, CD4 counts did nadir post ASCT in all French cohorts had more advanced disease as well as patients on or off HAART. This was seen at a median of chemotherapy refractory disease. In contrast, the Serrano 4.5 months in eight patients. The majority of patients did series includes first CR patients, and all patients remain in recover CD4 counts by 1 year post ASCT (Figure 1). Two remission, although follow-up is short. We have attempted patients have not yet recovered their counts and three died to utilize the same criteria that we use for HIV-negative before CD4 recovery. We saw transient increases in the lymphoma patients evaluated for transplant, for example, viral load in the first 2 months post transplant in the chemosensitive, disease or high-risk first remission disease. majority of patients. We saw persistent elevations in viral Of note, the majority of our patients had relapsed load in three patients who were noncompliant with lymphoma or failed to achieve a remission despite the HAART. One patient who was compliant still required upfront use of conventional chemotherapy and HAART. multiple changes in his regimen due to resistance. In the Hence, one cannot ascribe our results only to the use of French series, there were transient increases in viral load in HAART and its attendant improved response rates in two of nine patients with previously undetectable viral combination with chemotherapy. The patients who died loads. Although of note, there was no statistically from relapse in our series had poorly controlled disease, significantdifference in viral load or CD4 countpre and one with an anaplastic large-cell NHL and one with post ASCT for the 14 patients.30 In the nonmyeloablative Burkitt’s leukemia. Hence, the use of high-dose therapy allotransplant series, one patient had an abrupt rise in viral early in the course of chemotherapy responsive disease in load to 106 copies/ml during a period off HAART. these HIV-associated lymphomas may be of benefit. Resumption of antiretroviral therapy returned viral loads to undetectable levels. In the Spanish series, they report no increase in viral load with BMT conditioning as long as Conclusion HAART is maintained.35 It has been our observation that we have not seen long-term deleterious effects of ASCT in In summary, high-dose therapy with autologous stem cell patients who are compliant with HAART. However, this rescue is feasible in HIV-infected patients with lymphoma. also bespeaks to the need to evaluate patients closely pre Interactions between chemotherapy and HAART have not ASCT with regard to their ability to comply with their been a cause of significantincreases in regimen-related toxicity. However, the use of AZT should be avoided as it

275 250 1.0 225 0.9 200 0.8 175 0.7 150 0.6 125 0.5 CD4 counts 100 0.4 75

% Overall survival 0.3 50 Median CD4 Counts HIV-L (N = 19) 0.2 25 Overall survival 0.1 0 95% conf. interval 0 Lymphoma Apheresis ASCT 3 months 6 months 1 year Dx Day 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 Time (months) Surv time (months) post-ASCT Figure 1 Median CD4 counts HIV-L. Figure 2 Survival time post ASCT.

Bone Marrow Transplantation Stem cell transplants for HIV-positive lymphoma patients A Krishnan et al 747 Table 5 Future directions 2 Revision of the case definition of acquired immunodeficiency syndrome for national reporting – United States. MMWR Stem cell modification to Retrovirus genetic transduction 1985; 34: 373–375. confer resistance to HIV (AAV transduction methods) New conditioning regimens Nonmyeloablative regimens 3 Levine AM. Hodgkin’s disease in the setting of human Radioimmunotherapy (high-dose immunodeficiency virus infection. J Natl Cancer Inst Monogr ibritumomab with chemotherapy) 1998; 23: 37–42. Post transplant therapy Rituximab maintenance 4 Levine AM. Acquired immune deficiency syndrome Alternate stem cell sources Cord blood transplants related lymphoma; clinical aspects. Semin Oncol 2000; 27: with CCR5 – donors 442–453. 5 Senerviratne L, Espina BM, Nathwani BN et al. Clinical, immunologic and pathologic correlates of bone marrow can cause significant delays in engraftment. Infectious involvement in 291 patients with acquired immunodeficiency complications early post transplant are similar to HIV- syndrome related lymphoma. Blood 2001; 98: 2358–2363. negative patients; however, the use of appropriate prophy- 6 Tirelli U, Errante D, Dolcetti R et al. Hodgkin’s disease and laxis and surveillance is necessary to minimize the risk of immunodeficiency virus infection; clinicopathologic and viro- OIs. There appear to be no long-term deleterious effects on logic features of 114 patients from the Italian Cooperative the HIV infection, although short-term increases in HIV Group on AIDS and Tumours. J Clin Oncol 1995; 13: viral load and expected declines in CD4 counts are seen. 1758–1767. Lastly, the long-term remissions seen in many of these 7 Straus DJ, Juang J, Testa MA et al. Prognostic factors in the treatment of HIV associated non-Hodgkin’s lymphoma: patients suggest that this modality should be considered for analysis of the AIDS Clinical Trials Group protocol 142: low patients with relapsed chemosensitive disease. Thus, ASCT dose versus standard dose m-Bacod plus GMCSF. J Clin should be offered to patients with HIV and lymphoma. The Oncol 1998; 16: 3601–3606. HIV infection can be considered analogous to other chronic 8 Navarro JT, Ribera JM, Oriol A et al. International prognostic illnesses and should not be a barrier to transplantation. index is the best prognostic factor for survival in patients with Future directions of therapy will expand upon this initial AIDS related non-Hodgkin’s lymphoma treated with CHOP. favorable experience with transplantation in multiple ways A multivariate study of 46 patients. Haematologica 1998; 83: (Table 5). For instance, we have explored the use of high- 508–513. dose ibritumomab and chemotherapy with ASCT in HIV- 9 Kaplan LD, Straus DJ, Testa MA et al. Low-dose compared negative patients. It has been used in 18 patients and with standard dose m-BACOD chemotherapy for non-Hodgkin’s lymphoma associated with human immunodeficiency virus appears to be well tolerated; therefore, expanding its use to infection. N Engl J Med 1997; 336: 1641–1648. HIV-positive lymphoma patients may be warranted. 10 Oksenhendler E, Gerard L, Dubreuil ML et al. Intensive Alternately, allogeneic approaches using less dose intense chemotherapy (LNHIV 91 regimen) and GCSF for HIV regimens similar to those used in the HIV-negative setting associated non-Hodgkin’s lymphoma. Leukemia Lymphoma are being explored. Lastly, studies are being initiated to 2000; 39: 87–95. explore new ways of controlling the HIV infection such as 11 Levine AM, Li P, Cheung T et al. Chemotherapy consisting of genetic modification of autologous cells or transplanting DTIC with G-CSF in HIV infected patients with newly intrinsically HIV-resistant allogeneic stem cells such as diagnosed Hodgkin’s disease: a prospective multiinstitutional those that lack the CCR5 coreceptor necessary for HIV AIDS clinical trial group study (ACTG 149). J Acquir Immune Defic Syndr entry into the cell. The rationale for this is that better 2000; 24: 444–450. 12 Tirelli U, Errante D, Spina M et al. Second line chemotherapy control of the HIV infection may ultimately lead to lower in HIV related non-Hodgkin’s lymphoma. Cancer 1996; 77: chances of relapse of the lymphoma. 2127–2131. 13 Bi J, Espina BM, Tulpule A et al. High dose cytosine arabinoside and cisplatin regimens as salvage therapy for refractory or relapsed AIDS related non-Hodgkin’s lympho- Acknowledgements ma. J Acquir Immune Defic Syndr 2001; 28: 416–421. 14 Palella FJ, Delaney KM, Moorman AC et al. Declining We thank Dr David Smith and Jason Chapman, CRA for morbidity and mortality among patients with advanced human statistical support, Diana Garcia for manuscript preparation, immunodeficiency virus infection. HIV outpatient study Debra Vasquez, RN for transplant coordination and the clinical investigators. N Engl J Med 1998; 338: 853–860. staff in the Division of Hematology and Bone Marrow 15 Sparano JA, Anand K, Desai J et al. Effectof highly active Transplantation at the City of Hope. antiretroviral therapy on the incidence of HIV associated This work was supported in part by United States Public malignancies atan urban medical center. J Acquir Immune Health Science Grants CA 30206, CA 33572, A138592, and Defic Syndr 1999; 21: s18–s22. Grant MO1-RR-43 from the General Clinical Research Center 16 MocroftA, KatamaC, Johnson AM et al. AIDS across branch of the National Center for Research Resources, National Europe 1994–1998. The Euro SIDA Study. Lancet 2000; 356: Institutes of Health. AK is the recipient of a Lymphoma 291–296. Research Foundation of America award. 17 Appleby P, Beral V, Newton R et al. International collabora- tion on HIV and cancer: highly active antiretroviral therapy and incidence of cancer in human immunodeficiency infected adults. J Nat Cancer Inst 2000; 92: 1823–1830. References 18 Ratner L, Lee J, Tang S et al. Chemotherapy for HIV associated non-Hodgkin’s lymphoma in combination with 1 Roland ME, Stock PG. Review of solid-organ transplantation highly active antiretroviral therapy. J Clin Oncol 2001; 19: in HIV-infected patients. Transplant 2003; 75: 425–429. 2171–2178.

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Bone Marrow Transplantation